Antiviral agents

ABSTRACT

The invention provides a compound of formula I:  
                 
 
     wherein G, R 2 , and R 3  have any of the values defined in the specification, or a pharmaceutically acceptable salt thereof, as well as processes and intermediates useful for preparing such compounds or salts, and methods of treating a herpesvirus infection using such compounds or salts.

RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional PatentApplication Serial No. 60/248,865, filed Jan. 14, 2002.

FIELD OF THE INVENTION

[0002] The present invention provides7-oxo-4,7-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid benzylamidederivatives that are useful as antivirals, for example, as agentsagainst viruses of the herpes family.

BACKGROUND OF THE INVENTION

[0003] The herpesviruses comprise a large family of double stranded DNAviruses. They are also a source of the most common viral illnesses inman. Eight of the herpes viruses, herpes simplex virus types 1 and 2(HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus(HCMV), Epstein-Barr virus (EBV), and human herpes viruses 6, 7, and 8(HHV-6, HHV-7, and HHV-8), have been shown to infect humans.

[0004] HSV-1 and HSV-2 cause herpetic lesions on the lips and genitals,respectively. They also occasionally cause infections of the eye andencephalitis. HCMV causes birth defects in infants and a variety ofdiseases in immunocompromised patients such as retinitis, pneumonia, andgastrointestinal disease. VZV is the causative agent of chicken pox andshingles. EBV causes infectious mononucleosis. It can also causelymphomas in immunocompromised patients and has been associated withBurkitt's lymphoma, nasopharyngeal carcinoma, post-transplantlymphoproliferative disease (PTLD), and Hodgkins disease. HHV-6 is thecausative agent of roseola and may be associated with multiple sclerosisand chronic fatigue syndrome. HHV-7 disease association is unclear, butit may be involved in some cases of roseola. HHV-8 has been associatedwith Karposi's sarcoma, body cavity based lymphomas, and multiplemyeloma.

[0005] Infection by or reactivation of herpesviruses is associated withseveral cardiovascular diseases or conditions in the host such asatherosclerosis and restenosis resulting in inflammation of coronaryvessel walls. It is thought that in many patients suffering fromrestenosis following coronary atherectomy viral infection particularlyby CMV plays an important role in the proliferation of the disease.Atherosclerosis is believed to be associated with the overall infectiousdisease burden in the host and particularly by the herpesviruses such asHSV, CMV, and EBV.

[0006] Infection in the animal population (livestock and companion) bystrains of herpesviruses is endemic including cattle (Bovineherspesvirus 1-5, BHV), sheep (Ovine herpesvirus 1 and 2), dog (Canineherpesvirus 1), horse (Equine herpesvirus 1-8, EHV), cat (Felineherpesvirus 1, FHV), swine (pseudorabies virus, PRV), and many speciesof fowl. In the case of bovine herpesvirus infection, animals may sufferfrom ocular, respiratory, or digestive disorders. Pseudorabies is anextremely contagious viral pathogen infecting several species such ascattle, horses, dogs, cats, sheep, and goats leading to rapid death. Thevirus is benign in adult swine, however, it remains contagious and leadsto high mortality in pigs under three weeks. Infection of horses byequine herpesvirus may lead to neurological syndromes, respiratorydisease, and neonatal disease. Herpesvirus infection in cats leads tothe disease known as feline viral rhinotracheitis (FVR) which ischaracterized by rhinitis, tracheitis, laryngitis, and conjunctivitis.

INFORMATION DISCLOSURE

[0007] JP 08301849 discloses heterocyclic carboxamide compounds whichare reported to be useful as tachykinin receptor antagonists.

[0008] U.S. Pat. No. 6,239,142 discloses compounds having athieno[2,3-b]pyridine core which are reported to be useful for thetreatment of herpesvirus infections.

[0009] U.S. Pat. No. 5,352,685 discloses thieno[3,2-b]pyridinederivatives reported to be useful for the treatment of gastrointestinaldisorders. The compounds are also reported to be useful for thetreatment of anxiety and neuroses, and arrhythmia.

[0010] EP 269295 discloses thieno[3,2-b]pyridine compounds which arereported to be useful as cardiovascular agents.

[0011] EP 46990 discloses thieno[3,2-b]pyridine compounds which arereported to be useful as broad-spectrum antibacterials.

[0012] JP 57116077 discloses thieno[3,2-b]pyridine compounds which arereported to be useful as antibiotics.

[0013] JP 57142985 discloses thieno[3,2-b]pyridine compounds which arereported to be useful as antimicrobial agents.

[0014] In Drugs Future, 1999, 24, 966, there is disclosed athieno[3,2-b]pyridine compound MKC-733 which is reported to be useful asa 5-HT₃ receptor agonist for the treatment of constipation and GERD.

[0015] In Chem. Pharm. Bull. 1989, 37, 1256, there is disclosed athieno[3,2-b]pyridine compound 7 prepared and evaluated foranti-allergic activity. Compound 7 was reported to be inactive.

[0016] JP 08143573 A2 discloses thieno[3,2-b]pyridine compounds whichare reported to be useful for treatment of intestinal dysfunction.

[0017] U.S. Pat. No. 5,155,115 discloses compounds including certainthieno[3,2-b]pyridine compounds which are reported to be useful as S3antagonists for use as anti-emetics and anti-migraine agents.

[0018] U.S. Pat. No. 5,219,864 discloses compounds including certainthienopyridine compounds which are reported to be useful asimmunoregulators and antiosteoporosis drugs.

[0019] In Pharmazie 2000, 55, 595, there is disclosed the preparation ofcertain thienopyridine compounds which are reported to be useful asgyrase inhibitors for the inhibition of growth of bacteria.

[0020] In Tetrahedron 1987, 43, 3295, there is disclosed the preparationof certain thienopyridine compounds as potential antibacterials.

[0021] WO 00/07595 discloses certain thienopyridine compounds which arereported to be useful to treat sexual dysfunction.

[0022] WO 97/40846 discloses a pharmaceutical comprising an LH releasinghormone agonist and an LH releasing hormone antagonist. The disclosed LHreleasing hormone antagonists include an array of bicyclic compoundsthat include thienopyridines. The LH releasing hormone antagonists arenot reported to possess any antiviral activity.

[0023] EP 505058 discloses thienopyridone compounds that are reported topossess immunoregulating and bone absorption inhibiting activity.

[0024] Despite the above teachings, there still exists a need forcompounds with desirable antiviral activity.

SUMMARY OF THE INVENTION

[0025] 1. The present invention provides a compound of formula I:

[0026] wherein:

[0027] G is phenyl substituted with from one to five R¹ substituents;each R¹ is independently

[0028] (a) Cl,

[0029] (b) Br,

[0030] (c) F,

[0031] (d) cyano,

[0032] (d) C₁₋₇alkyl, or

[0033] (e) NO₂;

[0034] R² is

[0035] (a) H,

[0036] (b) R⁵,

[0037] (c) NR⁷R⁸,

[0038] (d) SO₂R⁹, or

[0039] (e) OR⁹;

[0040] R³ is

[0041] (a) H,

[0042] (b) halo,

[0043] (c) aryl,

[0044] (d) S(O)_(m)R⁶,

[0045] (e) (C═O)R⁶,

[0046] (f) (C═O)OH,

[0047] (g) (C═O)OR⁹,

[0048] (h) cyano,

[0049] (i) het, wherein the het is bound via a carbon atom,

[0050] (j) OR¹⁴,

[0051] (k) NR⁷R⁸,

[0052] (l) SR¹⁴,

[0053] (m) NHSO₂R¹²,

[0054] (n) C₁₋₇alkyl which is optionally partially unsaturated andoptionally substituted by one or more R¹¹ substituents, or

[0055] (o) C₃₋₈cycloalkyl which is optionally partially unsaturated andoptionally substituted by one or more R¹¹, or substituted by one or moreC₁₋₇alkyl which C₁₋₇alkyl is optionally substituted by one or more R¹¹;

[0056] R⁵ is

[0057] (a) (CH₂CH₂O)R¹⁰,

[0058] (b) het, wherein the het is bound via a carbon atom,

[0059] (c) aryl,

[0060] (d) C₁₋₇alkyl which is optionally partially unsaturated andoptionally substituted by one or more R¹¹ substituents, or

[0061] (e) C₃₋₈cycloalkyl which is optionally partially unsaturated andoptionally substituted by one or more R¹¹, or substituted by one or moreC₁₋₇alkyl which C₁₋₇alkyl is optionally substituted by one or more R¹¹;

[0062] R⁶ is

[0063] (a) C₁₋₇alkyl optionally substituted by aryl, bet, OR¹³, SR¹³,NR¹³R¹³, halo, or C₃₋₈cycloalkyl, which C₃₋₈cycloalkyl is optionallysubstituted with OR¹³,

[0064] (b) C₃₋₈cycloalkyl which is optionally partially unsaturated andoptionally substituted by one or more halo, OR¹³, SR¹³, or NR¹³R¹³substituents,

[0065] (c) NR⁷R⁸,

[0066] (d) aryl, or

[0067] (e) het, wherein the het is bound via a carbon atom;

[0068] R⁷ and R⁸ are independently

[0069] (a) H,

[0070] (b) aryl,

[0071] (c) C₁₋₇alkyl which is optionally partially unsaturated andoptionally substituted by one or more NR¹³R¹³, OR¹⁴, SR¹⁴, S(O)_(m)R⁹,P(═O)(OR¹⁴)(R¹⁴), CONR¹⁴R¹⁴, CO₂R¹³, (C═O)R⁹, het, aryl, cyano, or halosubstituents,

[0072] (d) C₃₋₈cycloalkyl which is optionally partially unsaturated andoptionally substituted by one or more halo, OR¹³, SR¹³, oxo, or NR¹³R¹³substituents,

[0073] (e) (C═O)R⁹, or

[0074] (f) R⁷ and R⁸ together with the nitrogen to which they areattached form a het;

[0075] R⁹ is

[0076] (a) aryl,

[0077] (b) het

[0078] (c) C₃₋₈cycloalkyl, or

[0079] (d) C₁₋₇alkyl which is optionally partially unsaturated andoptionally substituted by one or more NR¹³R¹³, OR¹⁴, SR¹⁴, halo,CONR¹³R¹³, CO₂R¹³, het, or aryl substituents;

[0080] R¹⁰ is

[0081] (a) H, or

[0082] (b) C₁₋₇alkyl optionally substituted by OH;

[0083] R¹¹ is

[0084] (a) OR¹⁴,

[0085] (b) SR¹⁴,

[0086] (c) NR⁷R⁸,

[0087] (d) halo,

[0088] (e) CONH₂,

[0089] (f) CONHR⁹,

[0090] (g) CONR⁹R⁹,

[0091] (h) CO₂H,

[0092] (i) CO₂R⁹,

[0093] (j) het,

[0094] (k) aryl,

[0095] (l) cyano,

[0096] (m) oxo,

[0097] (n) SO_(m)R⁶, or

[0098] (o) P(═O)(OR¹⁴)(R¹⁴);

[0099] R¹² is

[0100] (a) H,

[0101] (b) het,

[0102] (c) aryl,

[0103] (d) C₃₋₈cycloalkyl optionally substituted with R¹¹, or

[0104] (e) C₁₋₇alkyl optionally substituted with R¹¹;

[0105] R¹³ is

[0106] (a) H, or

[0107] (b) C₁₋₇alkyl;

[0108] R¹⁴ is

[0109] (a) H,

[0110] (b) aryl,

[0111] (c) het,

[0112] (d) C₁₋₇alkyl which is optionally partially unsaturated andoptionally substituted by aryl, het, OR¹³, SR¹³, NR¹³R¹³, halo, orC₃₋₈cycloalkyl which C₃₋₈cycloalkyl is optionally substituted by one ormore OR¹³, or

[0113] (e) C₃₋₈cycloalkyl which is optionally partially unsaturated andoptionally substituted by one or more halo, OR¹³, SR¹³, or NR¹³R¹³substituents;

[0114] R¹⁵ is

[0115] (a) H,

[0116] (b) halo,

[0117] (c) OR¹³,

[0118] (d) SR¹³,

[0119] (e) NR¹³R¹³,

[0120] (f) O(CH₂CH₂O)_(n)R¹⁰,

[0121] a. phenyl,

[0122] b. cyano,

[0123] c. nitro,

[0124] d. CONR¹³R¹³,

[0125] e. CO₂R¹³,

[0126] f. S(O)_(m)NR¹³R¹³,

[0127] g. CONHR¹³,

[0128] h. S(O)_(m)R¹⁰,

[0129] i. NR¹³COR¹³,

[0130] j. C₁₋₇alkyl which is optionally partially unsaturated andoptionally substituted with one or more oxo, phenyl, 4-morpholine, OR¹³,SR¹³, NR¹³R¹³, halo, CO₂R¹³, CONR¹³R¹³, or C₃₋₈cycloalkyl whichC₃₋₈cycloalkyl is optionally substituted by one or more OR¹³, or

[0131] k. C₃₋₈cycloalkyl which is optionally partially unsaturated andoptionally substituted by one or more oxo, halo, OR¹³, SR¹³, C₁₋₇alkyl,CONH₂ or NR¹³R¹³ substituents; or

[0132] l. pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, pyridazinyl,imidazolyl, or pyrazolyl;

[0133] each i is independently 2, 3, or 4;

[0134] each n is independently 1, 2, 3, 4 or 5;

[0135] each m is independently 1 or 2;

[0136] wherein any aryl other than G is optionally substituted with oneor more R¹⁵ substituents; and

[0137] wherein any het is optionally substituted with one or more ═O,═N—OR¹³, or R¹⁵ substituents; or

[0138] a pharmaceutically acceptable salt thereof.

[0139] In another aspect, the present invention also provides:

[0140] a pharmaceutical composition comprising a compound of formula I,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient (the composition preferably comprises an effectiveantiviral amount of the compound or salt);

[0141] a method of treating a herpesviral infection, comprisingadministering to a mammal (e.g. a human) in need of such treatment, acompound of formula I or a pharmaceutically acceptable salt thereof;

[0142] a method of treating atherosclerosis or restenosis comprisingadministering to a mammal (e.g. a human) in need of such treatment, acompound of formula I or a pharmaceutically acceptable salt thereof;

[0143] a method for inhibiting a viral DNA polymerase, comprisingcontacting (in vitro or in vivo) the polymerase with an effectiveinhibitory amount of a compound of formula I, or a pharmaceuticallyacceptable salt thereof.

[0144] a compound of formula I or a pharmaceutically acceptable saltthereof for use in medical treatment (e.g. the treatment of aherpesviral infection or the treatment of atherosclerosis orrestenosis);

[0145] the use of a compound of formula I or a pharmaceuticallyacceptable salt thereof to prepare a medicament for treating aherpesviral infection in a mammal (e.g. a human);

[0146] the use of a compound of formula I or a pharmaceuticallyacceptable salt thereof to prepare a medicament for treatingatherosclerosis or restenosis in a mammal (e.g. a human); and

[0147] the use of a compound of formula I or a pharmaceuticallyacceptable salt thereof to prepare a medicament for inhibiting a viralDNA polymerase in a mammal (e.g. a human).

[0148] The invention also provides novel intermediates and processesdisclosed herein that are useful for preparing compounds of formula I,including the generic and specific intermediates as well as thesynthetic processes described in the Charts and Examples herein.

DETAILED DESCRIPTION OF THE INVENTION

[0149] The following definitions are used, unless otherwise described:halo is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, etc. denote bothstraight and branched groups; but reference to an individual radicalsuch as “propyl” embraces only the straight chain radical, a branchedchain isomer such as “isopropyl” being specifically referred to. Whenalkyl can be partially unsaturated, the alkyl chain may comprise one ormore (e.g. 1, 2, 3, or 4) double or triple bonds in the chain.

[0150] “Aryl” denotes a phenyl radical or an ortho-fused bicycliccarbocyclic radical having about nine to ten ring atoms in which atleast one ring is aromatic.

[0151] “Het” is a 4-16 membered saturated or unsaturated monocyclic,bicyclic, or tricyclic ring system having 1, 2, 3, or 4 heteroatoms,such as oxygen (—O—), sulfur (—S—), oxygenated sulfur such as sulfinyl(S═O) and sulfonyl (S(═O)₂), or nitrogen, or an N-oxide thereof. Hetincludes “heteroaryl”, which encompasses a radical attached via a ringcarbon of a monocyclic aromatic ring containing five or six ring atomsconsisting of carbon and 1, 2, 3, or 4 heteroatoms, such as non-peroxideoxygen (—O—), sulfur (—S—), oxygenated sulfur such as sulfinyl (S═O) andsulfonyl (S(═O)₂), or nitrogen N(X) wherein X is absent or is H, O,C₁₋₄alkyl, phenyl or benzyl, as well as a radical of an ortho-fusedbicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing apropylene, trimethylene, or tetramethylene diradical thereto. Whenheteroaryl is an ortho-fused benz-derivative it can be attached via anyatom in an aromatic ring (e.g. an atom of the benz-ring).

[0152] “Partially unsaturated”, for example, a C₁₋₇alkyl which isoptionally partially unsaturated, means the named substituent has one ormore unsaturations, such as one or more double bonds, one or more triplebonds, or both.

[0153] The terms “include”, “for example”, “such as”, and the like areused illustratively and are not intended to limit the present invention.

[0154] The indefinite articles “a” and “an” mean “at least one” or “oneor more” when used in this application, including the claims, unlessspecifically indicated otherwise.

[0155] “Optional” or “optionally” mean that the subsequently describedevent or condition may but need not occur, and that the descriptionincludes instances where the event or condition occurs and instances inwhich it does not. For example, “optionally substituted” means that thenamed substituent may be present but need not be present, and thedescription includes situations where the named substituent is includedand situations where the named substituent is not included.

[0156] “Mammal” denotes humans and animals. Animals specifically referto, for example, food animals or companion animals.

[0157] It will be appreciated by those skilled in the art that compoundsof the invention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, tautomeric, orstereoisomeric form, or mixture thereof, of a compound of the invention,which possesses the useful properties described herein, it being wellknown in the art how to prepare optically active forms (for example, byresolution of the racemic form by recrystallization techniques, bysynthesis from optically-active starting materials, by chiral synthesis,or by chromatographic separation using a chiral stationary phase) andhow to determine antiviral activity using the standard tests describedherein, or using other similar tests which are well known in the art. Inparticular, it is understood that compounds of formula I wherein R² ishydrogen can exist in the corresponding tautomeric “enol” form asillustrated in the following formula

[0158] and that such tautomers are included as compounds of theinvention.

[0159] The carbon atom content of various hydrocarbon-containingmoieties is indicated by a prefix designating a lower and upper numberof carbon atoms in the moiety, i.e., the prefix C_(i-j) indicates amoiety of the integer ‘i” to the integer “j” carbon atoms, inclusive.Thus, for example, C₁₋₇alkyl refers to alkyl of one to seven carbonatoms, inclusive.

[0160] The compounds of the present invention are generally namedaccording to the IUPAC or CAS nomenclature system. Abbreviations whichare well known to one of ordinary skill in the art may be used (e.g.“Ph” for phenyl, ‘Me” for methyl, “Et” for ethyl, “h” for hour or hoursand “rt” for room temperature).

[0161] Specific and preferred values listed below for radicals,substituents, and ranges, are for illustration only; they do not excludeother defined values or other values within defined ranges for theradicals and substituents. The compounds of the invention includecompounds of formula I having any combination of the values, specificvalues, more specific values, and preferred values described herein.

[0162] Specifically, C₁₋₇alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, or heptyl;C₃₋₈cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, or cyclooctyl; C₁₋₇alkoxy can be methoxy, ethoxy, propoxy,isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy,hexyloxy, 1-methylhexyloxy, or heptyloxy; C₁₋₇alkanoyl can be acetyl,propanoyl, butanoyl, pentanoyl, 4-methylpentanoyl, hexanoyl, orheptanoyl; aryl can be phenyl, indenyl, or naphthyl.

[0163] “Heteroaryl” can be pyridine, thiophene, furan, pyrazoline,pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl,2-quinolyl, 3-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl,2-quinazolinyl, 4-quinazolinyl, 2-quinoxalinyl, 1-phthalazinyl,4-oxo-2-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl,2-oxazolyl, 4-oxazolyl, 4-oxo-2-oxazolyl, 5-oxazolyl,4,5,-dihydrooxazole, 1,2,3-oxathiole, 1,2,3-oxadiazole,1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole,2-indolyl, 3-indolyl, 3-indazolyl, 2-benzoxazolyl, 2-benzothiazolyl,2-benzimidazolyl, 2-benzofuranyl, 3-benzofuranyl, benzoisothiazole,benzisoxazole, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl,3-pyrrolyl, 3-isopyrrolyl, 4-isopyrrolyl, 5-isopyrrolyl,1,2,3,-oxathiazole-1-oxide, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,5-oxo-1,2,4-oxadiazol-3-yl, 1,2,4-thiadiazol-3-yl,1,2,4-thiadiazol-5-yl, 3-oxo-1,2,4-thiadiazol-5-yl,1,3,4-thiadiazol-5-yl, 2-oxo-1,3,4-thiadiazol-5-yl, 1,2,4-triazol-3-yl,1,2,4-triazol-5-yl, 1,2,3,4-tetrazol-5-yl, 5-oxazolyl, 1-pyrrolyl,1-pyrazolyl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 1-tetrazolyl,1-indolyl, 1-indazolyl, 2-isoindolyl, 7-oxo-2-isoindolyl,1-purinyl,3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl, 1,3,4,-oxadiazole,4-oxo-2-thiazolinyl, or 5-methyl-1,3,4-thiadiazol-2-yl, thiazoledione,1,2,3,4-thiatriazole, 1,2,4-dithiazolone. Each of these moieties may besubstituted as appropriate or can include and their correspondingN-oxides as appropriate.

[0164] When C₁₋₇alkyl is partially unsaturated, it can specifically bevinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl,2-pentynyl, 3-pentynyl, 4-pentynyl, 5-hexene-1-ynyl, 2-hexynyl,3-hexynyl, 4-hexynyl, or 5-hexynyl.

[0165] A specific value for “Het” is a four- (4), five- (5), six- (6),or seven- (7) membered saturated or unsaturated monocyclic, bicyclic, ortricyclic ring system having 1, 2, 3, or 4 heteroatoms, such as oxygen(—O—), sulfur (—S—), oxygenated sulfur such as sulfinyl (S═O) andsulfonyl (S(═O)₂), or nitrogen, and which ring system is optionallyfused to a benzene ring or an N-oxide thereof.

[0166] Another specific value for Het is a five- (5), six- (6), orseven- (7) membered saturated or unsaturated ring containing 1, 2, 3, or4 heteroatoms, for example, non-peroxide oxy, thio, sulfinyl, sulfonyl,and nitrogen; as well as a radical of an ortho-fused bicyclicheterocycle of about eight to twelve ring atoms derived therefrom,particularly a benz-derivative or one derived by fusing a propylene,trimethylene, tetramethylene or another monocyclic het diradicalthereto.

[0167] Specific values of “het” are, but not limited to, pyridine,thiophene, furan, pyrazoline, pyrimidine, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl,4-pyridazinyl, 3-pyrazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl,4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4-oxo-2-oxazolyl,5-oxazolyl, 1,2,3-oxathiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,1,2,5-oxadiazole, 1,3,4-oxadiazole, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole, 2-furanyl,3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isopyrrolyl,4-isopyrrolyl, 5-isopyrrolyl, 1,2,3,-oxathiazole-1-oxide,1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 5-oxo-1,2,4-oxadiazol-3-yl,1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,3-oxo-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-5-yl,2-oxo-1,3,4-thiadiazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl,1,2,3,4-tetrazol-5-yl, 5-oxazolyl, 3-isothiazolyl, 4-isothiazolyl,5-isothiazolyl, 1,3,4,-oxadiazole, 4-oxo-2-thiazolinyl,5-methyl-1,3,4-thiadiazol-2-yl, thiazoledione, 1,2,3,4-thiatriazole,1,2,4-dithiazolone, phthalimide, quinolinyl, morpholinyl, benzoxazoyl,diazinyl, triazinyl, quinolinyl, quinoxalinyl, naphthyridinyl,azetidinyl, pyrrolidinyl, hydantoinyl, oxathiolanyl, dioxolanyl,imidazolidinyl, azabicyclo[2.2.1]heptyl, and optionally theircorresponding N-oxides.

[0168] A specific value for G is phenyl substituted with one R¹.

[0169] A more specific value for G is phenyl substituted with two R¹.

[0170] Another specific value for G is phenyl substituted with three R¹.

[0171] Another specific value for G is 4-chlorophenyl.

[0172] Another specific value for G is 4-fluorophenyl.

[0173] Another specific value for G is 3,4-dichlorophenyl.

[0174] Another specific value for G is 3,4-difluorophenyl.

[0175] Another specific value for G is 2,4-dichlorophenyl.

[0176] Another specific value for G is 2,4-difluorophenyl.

[0177] Another specific value for G is 4-chloro-2-fluorophenyl.

[0178] Another specific value for G is 2-chloro-4-fluorophenyl.

[0179] Another specific value for G is 3,4,5-trifluorophenyl.

[0180] Another specific value for G is 4-bromophenyl.

[0181] Another specific value for G is 4-methylphenyl.

[0182] Another specific value for G is 4-cyanophenyl.

[0183] Another specific value for G is 4-nitrophenyl.

[0184] A specific value for R¹ is F, Cl, or Br.

[0185] A more specific value for R¹ is Cl.

[0186] Another more specific value for R¹ is 4-Cl.

[0187] Another specific value for R¹ is methyl.

[0188] A specific value for R¹ is H.

[0189] Another specific value for R² is C₁₋₇alkyl which is optionallypartially unsaturated and is optionally substituted with one or more R¹¹substituents.

[0190] Another specific value for R² is methyl.

[0191] Another specific value for R² is ethyl.

[0192] A specific value for R³ is H, halo, aryl, S(O)_(m)R⁶, (C═O)R⁶,(C═O)OH, (C═O)OR⁹, cyano, OR¹⁴, NR⁷R⁸SR¹⁴, or NHSO₂R¹².

[0193] Another specific value for R³ is C₁₋₇alkyl which is optionallypartially unsaturated and optionally substituted with one or more R¹¹,OR¹³, SR¹⁰, SR¹³, NR⁷R⁸, halo, C₁₋₇alkanoyl, and SO_(m)R⁹ substituents.

[0194] A specific value for R³ isC₁₋₇alkyl which is optionally partiallyunsaturated and optionally substituted with one or more R¹¹substituents, or C₃₋₈cycloalkyl which is optionally partiallyunsaturated and optionally substituted by one or more R¹¹ or C₁₋₇alkylsubstituents.

[0195] Another specific value for R³ is C₁₋₇alkyl which is optionallypartially unsaturated and optionally substituted with one or more R¹¹substituents, or C₃₋₈cycloalkyl which is optionally partiallyunsaturated and optionally substituted by one or more R¹¹ or C₁₋₇alkylsubstituents.

[0196] Another specific value for R³ is (Z or E) —CH═CH(CH₂)_(n)R_(a) or—C═C(CH₂)_(n)R_(a) wherein R_(a) is R¹¹, OR¹³, SR¹⁰, SR¹³, NR⁷R⁸, halo,C₁₋₇alkanoyl, or SO_(m)R⁹.

[0197] Another specific value for R³ is CH₂NR⁷R⁸.

[0198] A more specific value for R³ is CH₂NR⁷R⁸ where R⁷ is C₁₋₇alkyl,and R⁸ is C₁₋₇alkyl which is optionally partially unsaturated and isoptionally substituted by one or more NR¹³R¹³, OR¹⁴, SR¹⁴, S(O)_(m)R⁹,CONR¹³R¹³, CO₂R¹³, (C═O)R⁹, het, aryl, cyano, or halo substituents.

[0199] Another specific value for R³is CH₂NR⁷R⁸ where R⁷ is methyl, andR⁸ is ethyl substituted with aryl or het, and an OR¹⁴.

[0200] Another specific value for R³ is C₁₋₇alkyl which comprises onedouble bond and is optionally substituted by one or more R¹¹substituents.

[0201] Another specific value for R³is C₁₋₇alkyl which comprises onetriple bond and is optionally substituted by one or more R¹¹substituents.

[0202] Another specific value for R³ is het, wherein the het is bound tothe thieno ring via a carbon atom.

[0203] Another specific value for R³ is het, wherein the het is bound tothe thieno ring via a nitrogen atom.

[0204] Another specific value for R³ is H.

[0205] Another specific value for R³ is 3-hydroxy-propyn-1-yl.

[0206] Another specific value for R³ is hydroxymethyl.

[0207] Another specific value for R³ isN-methyl-N-{2-(4-hydroxyphenyl)-2-hydroxy-ethyl}aminomethyl.

[0208] Another specific value for R³ is morpholinomethyl.

[0209] Another specific value for R³ isN-methyl-N-{2-(3-hydroxyphenyl)-2-hydroxy-ethyl}aminomethyl.

[0210] Another specific value for R³ isN-methyl-N-{2-(3-methoxyphenyl)-2-hydroxy-ethyl}aminomethyl.

[0211] Another specific value for R³ isN-methyl-N-(2-furan-2-yl-2-hydroxy-ethyl) aminomethyl.

[0212] Another specific value for R³ isN-methyl-N-{2-phenyl-2-hydroxy-ethyl}aminomethyl.

[0213] Another specific value for R³ isN-methyl-N-{2-(1,3-thiazol-2-yl)ethyl}aminomethyl.

[0214] Another specific value for R³ isN-methyl-N-{2-(4-methylsulfonylphenyl)-2-hydroxy-ethyl}aminomethyl.

[0215] Another specific value for R³ isN-methyl-N-{2-(pyridin-2-yl)-2-hydroxy-ethyl}aminomethyl.

[0216] A specific value for R⁵ is (CH₂CH₂O)_(i)R¹⁰.

[0217] A specific value for R⁵ is C₁₋₇alkyl which is optionallypartially unsaturated and is optionally substituted by one or more R¹¹substituents, or C₃₋₈cycloalkyl which is optionally partiallyunsaturated and optionally substituted by one or more R¹¹ or C₁₋₇alkylsubstituents and optionally substituted with R¹¹.

[0218] A specific group of compounds are compounds of formula I whereinG is phenyl substituted with one or two R¹ groups when R² and R³ areboth C₁₋₇alkyl which C₁₋₇alkyl substituents are optionally partiallyunsaturated and optionally substituted with one or more R¹¹substituents.

[0219] Another specific group of compounds are compounds of formula Iwherein specific value for G is phenyl substituted at the 4-positionwith R¹ when R³ is C₁₋₇alkyl which C₁₋₇alkyl is optionally substitutedby NR⁷R⁸; and R² is CH₃.

[0220] Another specific value for G is 4-chlorophenyl when R³ isCH₂N(CH₃)CH₂CH(OH)aryl or CH₂N(CH₃)CH₂CH(OH)het, and R² is CH₃.

[0221] A specific compound of the present invention isN-(4-Chlorobenzyl)-7-hydroxythieno[3,2-b]pyridine-6-carboxamide.

[0222] Another specific compound of the present invention isN-(4-Chlorobenzyl)-4-ethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0223] Another specific compound of the present invention isN-(4-chlorobenzyl)-2-(3-hydroxyprop-1-ynyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0224] Another specific compound of the present invention isN-(4-chlorobenzyl)-4-methyl-2-(morpholin-4-ylmethyl)-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0225] Another specific compound of the present invention isN-(4-chlorobenzyl)-2-{[[2-hydroxy-2-(3-methoxyphenyl)ethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0226] Another specific compound of the present invention isN-(4-chlorobenzyl)-2-{[[2-(2-furyl)-2-hydroxyethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0227] Another specific compound of the present invention isN-(4-chlorobenzyl)-2-{[(2-hydroxy-2-phenylethyl)(methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0228] Another specific compound of the present invention isN-(4-chlorobenzyl)-2-{[[2-hydroxy-2-(1,3-thiazol-2-yl)ethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0229] Another specific compound of the present invention isN-(4-chlorobenzyl)-2-{[{2-hydroxy-2-[4-(methylsulfonyl)phenyl]ethyl}(methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0230] Another specific compound of the present invention isN-(4-chlorobenzyl)-2-{[(2-hydroxy-2-pyridin-2-ylethyl)(methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0231] A specific compound of the invention is a compound of formula Iwherein: G is phenyl substituted with from one to five R¹ substituents;each R¹ is independently

[0232] (a) Cl,

[0233] (b) Br,

[0234] (c) F,

[0235] (d) cyano,

[0236] (e) C₁₋₇alkyl, or

[0237] (f) NO₂;

[0238] R² is

[0239] (a) H,

[0240] (b) R⁵,

[0241] (c) NR⁷R⁸,

[0242] (d) SO₂R⁹, or

[0243] (e) OR⁹;

[0244] R³ is

[0245] (a) H,

[0246] (b) halo,

[0247] (c) aryl,

[0248] (d) S(O)_(m)R⁶,

[0249] (e) (C═O)R⁶,

[0250] (f) (C═O)OH,

[0251] (g) (C═O)OR⁹,

[0252] (h) cyano,

[0253] (i) het, wherein the het is bound via a carbon atom,

[0254] (j) OR¹⁴,

[0255] (k) NR⁷R⁸

[0256] (l) SR¹⁴,

[0257] (m) NHSO₂R¹²,

[0258] (n) C₁₋₇alkyl which is optionally partially unsaturated andoptionally substituted by one or more R¹¹ substituents, or

[0259] (o) C₃₋₈cycloalkyl which is optionally partially unsaturated andoptionally substituted by one or more R¹¹, or substituted by one or moreC₁₋₇alkyl which C₁₋₇alkyl is optionally substituted by one or more R¹¹;

[0260] R¹ is

[0261] (a) (CH₂CH₂O)R¹⁰,

[0262] (b) het, wherein the het is bound via a carbon atom,

[0263] (c) aryl,

[0264] (d) C₁₋₇alkyl which is optionally partially unsaturated andoptionally substituted by one or more R¹¹ substituents, or

[0265] (e) C₃₋₈cycloalkyl which is optionally partially unsaturated andoptionally substituted by one or more R¹¹, or substituted by one or moreC₁₋₇alkyl which C₁₋₇alkyl is optionally substituted by one or more R¹¹;

[0266] R⁶ is

[0267] (a) C₁₋₇alkyl optionally substituted by aryl, het, OR¹³, SR¹³,NR¹³R¹³, halo, or C₃₋₈cycloalkyl, which C₃₋₈cycloalkyl is optionallysubstituted with OR¹³,

[0268] (b) C₃₋₈cycloalkyl which is optionally partially unsaturated andoptionally substituted by one or more halo, OR¹³, SR¹³, or NR¹³R¹³substituents,

[0269] (c) NR⁷R⁸,

[0270] (d) aryl, or

[0271] (e) het, wherein the het is bound via a carbon atom;

[0272] R⁷ and R⁸ are independently

[0273] (a) H,

[0274] (b) aryl,

[0275] (c) C₁₋₇alkyl which is optionally partially unsaturated andoptionally substituted by one or more NR¹³R¹³, OR¹⁴, SR¹⁴, S(O)_(m)R⁹,P(═O)(OR¹⁴)(R¹⁴), CONR¹³R¹³, CO₂R¹³, (C═O)R⁹, het, aryl, cyano, or halosubstituents,

[0276] (d) C₃₋₈cycloalkyl which is optionally partially unsaturated andoptionally substituted by one or more halo, OR¹³, SR¹³, oxo, or NR¹³R¹³substituents,

[0277] (e) (C═O)R⁹, or

[0278] (f) R⁷ and R⁸ together with the nitrogen to which they areattached form a het;

[0279] R⁹ is

[0280] (a) aryl,

[0281] (b) het

[0282] (c) C₃₋₈cycloalkyl, or

[0283] (d) C₁₋₇alkyl which is optionally partially unsaturated andoptionally substituted by one or more NR¹³R¹³, OR¹⁴, SR¹⁴, halo,CONR¹³R¹³, CO₂R¹³, het, or aryl substituents;

[0284] R¹⁰ is

[0285] (a) H, or

[0286] (b) C₁₋₇alkyl optionally substituted by OH;

[0287] R¹¹ is

[0288] (a) OR¹⁴,

[0289] (b) SR¹⁴,

[0290] (c) NR⁷R⁸,

[0291] (d) halo,

[0292] (e) CONH₂,

[0293] (f) CONHR⁹,

[0294] (g) CONR⁹R⁹,

[0295] (h) CO₂H,

[0296] (i) CO₂R⁹,

[0297] (j) het,

[0298] (k) aryl,

[0299] (l) cyano,

[0300] (m) oxo,

[0301] (n) SO_(m)R⁶, or

[0302] (o) P(═O)(OR¹⁴)(R¹⁴);

[0303] R¹² is

[0304] (a) H,

[0305] (b) het,

[0306] (c) aryl,

[0307] (d) C₃₋₈cycloalkyl optionally substituted with R¹¹, or

[0308] (e) C₁₋₇alkyl optionally substituted with R¹¹;

[0309] R¹³ is

[0310] (a) H, or

[0311] (b) C₁₋₇alkyl;

[0312] R¹⁴ is

[0313] (a) H,

[0314] (b) aryl,

[0315] (c) het, wherein the het is bound through a carbon atom,

[0316] (d) C₁₋₇alkyl which is optionally partially unsaturated andoptionally substituted by aryl, het, OR¹³, SR¹³, NR¹³R¹³, halo, orC₃₋₈cycloalkyl which C₃₋₈cycloalkyl is optionally substituted by one ormore OR¹³, or

[0317] (e) C₃₋₈cycloalkyl which is optionally partially unsaturated andoptionally substituted by one or more halo, OR¹³, SR¹³, or NR¹³R¹³substituents;

[0318] R¹⁵ is

[0319] (a) H,

[0320] (b) halo,

[0321] (c) OR¹³,

[0322] (d) SR¹³,

[0323] (e) NR¹³R¹³,

[0324] (f) O(CH₂CH₂O)_(n)R¹⁰,

[0325] (g) phenyl,

[0326] (h) cyano,

[0327] (i) nitro,

[0328] (j) CONR¹³R¹³,

[0329] (k) CO₂R¹³,

[0330] (l) S(O)_(m)NR¹³R¹³,

[0331] (m) CONHR¹³,

[0332] (n) C₁₋₇alkyl which is optionally partially unsaturated andoptionally substituted with oxo, phenyl, 4-morpholine, OR¹³, SR¹³,NR¹³R¹³, halo, CO₂R¹³, CONR¹³R¹³, or C₃₋₈cycloalkyl which C₃₋₈cycloalkylis optionally substituted by one or more OR¹³, or

[0333] (o) C₃₋₈cycloalkyl which is optionally partially unsaturated andoptionally substituted by one or more oxo, halo, OR¹³, SR¹³, C₁₋₇alkyl,CONH₂ or NR¹³R¹³substituents;

[0334] each i is independently 2, 3, or 4;

[0335] each n is independently 1, 2, 3, 4 or 5;

[0336] each m is independently 1 or 2;

[0337] wherein any aryl other than G is optionally substituted with oneor more R¹⁵ substituents; and

[0338] wherein any het is optionally substituted with one or more ═O,═N—OR¹³, or R¹⁵ substituents; or

[0339] a pharmaceutically acceptable salt thereof.

[0340] The present invention includes a pharmaceutically acceptable saltof any of the above mentioned compounds.

[0341] A specific compound of the invention is a compound of formula IV:

[0342] wherein:

[0343] R² and G have any of the values or specific values describedherein;

[0344] R¹⁶ is

[0345] (a) H,

[0346] (b) aryl,

[0347] (c) C₁₋₇alkyl which is optionally partially unsaturated and isoptionally substituted by one or more NR¹³R¹³, OR¹⁴, or SR¹⁴,S(O)_(m)R⁹, CONR¹⁴R¹⁴, CO₂R¹³, (C═O)R⁹, het, aryl, cyano, or halosubstituents,

[0348] (d) C₃₋₈cycloalkyl which is optionally partially unsaturated andis optionally substituted by one or more halo, OR¹³, SR¹³, oxo, orNR¹³R¹³substituents, or

[0349] (e) (C═O)R⁹;

[0350] R¹⁷ is

[0351] (a) aryl, or

[0352] (b) het;

[0353] R⁹ is

[0354] (a) aryl,

[0355] (b) het

[0356] (c) C₃₋₈cycloalkyl, or

[0357] (d) C₁₋₇alkyl which is optionally partially unsaturated andoptionally substituted by one or more NR¹³R¹³, OR¹⁴, SR¹⁴, halo,CONR¹³R¹³, CO₂R¹³, het, or aryl substituents;

[0358] R¹⁰ is

[0359] (a) H, or

[0360] (b) C₁₋₇alkyl optionally substituted by OH;

[0361] R¹⁰ is

[0362] (a) H, or

[0363] (b) C₁₋₇alkyl;

[0364] R⁴ is

[0365] (a) H,

[0366] (b) aryl,

[0367] (c) het,

[0368] (d) C₁₋₇alkyl which is optionally partially unsaturated andoptionally substituted by aryl, het, OR¹³, SR¹³, NR¹³R¹³, halo, orC₃₋₈cycloalkyl which C₃₋₈cycloalkyl is optionally substituted by one ormore OR¹³, or

[0369] (e) C₃₋₈cycloalkyl which is optionally partially unsaturated andoptionally substituted by one or more halo, OR¹³, SR¹³, or NR¹³R¹³substituents; and

[0370] R¹⁵ is

[0371] (a) H,

[0372] (b) halo,

[0373] (c) OR¹³,

[0374] (d) SR¹³,

[0375] (e) NR¹³R¹³,

[0376] (f) O(CH₂CH₂O)_(n)R¹⁰,

[0377] (g) phenyl,

[0378] (h) cyano,

[0379] (i) nitro,

[0380] (j) CONR¹³R¹³,

[0381] (k) CO₂R¹³,

[0382] (l) S(O)_(m)NR¹³R¹³,

[0383] (m) CONHR¹³,

[0384] (n) S(O)_(m)R¹⁰,

[0385] (o) NR¹³COR¹³,

[0386] (p) C₁₋₇alkyl which is optionally partially unsaturated andoptionally substituted with one or more oxo, phenyl, 4-morpholine, OR¹³,SR¹³, NR¹³R¹³, halo, CO₂R¹³, CONR¹³R¹³, or C₃₋₈cycloalkyl whichC₃₋₈cycloalkyl is optionally substituted by one or more OR¹³, or

[0387] (q) C₃₋₈cycloalkyl which is optionally partially unsaturated andoptionally substituted by one or more oxo, halo, OR¹³, SR¹³, C₁₋₇alkyl,CONH₂ or NR¹³R¹³ substituents; or

[0388] (r) pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, pyridazinyl,imidazolyl, or pyrazolyl;

[0389] each m is independently 1 or 2;

[0390] each n is independently 1, 2, 3, 4, or 5;

[0391] wherein any aryl other than G is optionally substituted with oneor more R¹⁵ substituents; and

[0392] wherein any het is optionally substituted with one or more ═O,═N—OR¹³, or R¹⁵ substituents; or

[0393] a pharmaceutically acceptable salt thereof.

[0394] A specific compound of formula IV is a compound of formula V:

[0395] or a pharmaceutically acceptable salt thereof.

[0396] Another specific compound of formula IV is a compound of formulaVI:

[0397] or a pharmaceutically acceptable salt thereof.

[0398] A more specific compound of the invention is a compound offormula IV wherein the hydroxy group has the same absolute configurationas the compound prepared at Example 21.

[0399] Specifically, the invention provides the synthetic processes andintermediates described in Preparations and Examples hereinbelow (e.g.Preparations 2, 3, 9, 13, 14, and 15).

[0400] The following Charts A-F describe the preparation of thecompounds of the present invention. All of the starting materials areprepared by procedures described in these charts or by proceduresanalogous thereto, which would be well known to one of ordinary skill inorganic chemistry. All of the final compounds of the present inventionare prepared by procedures described in these charts, by proceduresanalogous thereto, or by procedures which are known to one of ordinaryskill in organic chemistry. All of the variables used in the charts areas defined below or as in the claims.

[0401] Ester A-1 (commercially available, e.g. from Acros-USA) can besaponified with aqueous sodium hydroxide and then acidified with aceticacid. The resulting 3-aminothiophene can be reacted with diethylethoxymethylenemalonate (DEEM) to afford aminomethylene malonate of theformula A-2. Refluxing in diphenyl ether induces cyclization to thecompound of formula A-3. Reaction with excess strong base, such aslithium diisopropylamide (LDA), followed by quenching with a suitablepolar solvent and a source of the formyl group, such asdimethylformamide (DMF), provides the carboxaldehyde of formula A-4.N-Alkylation with optionally substituted alkyl halides occurs in DMF inthe presence of potassium carbonate to afford compounds of formula A-5.Reduction with sodium triacetoxyborohydride produces alcohols of theformula A-6, which are reacted with substituted benzylamines to affordamides of formula A-7. The alcohols can be converted to chlorides offormula A-8 by reaction with, for example, methanesulfonyl chloride(MsCl) in the presence of dimethylaminopyridine (DMAP). Displacement ofthe chloride with optionally substituted nucleophiles NuH, for exampleNu=R¹⁴O, R¹⁴S or R⁷R⁸N, in the presence of a suitable base yieldscompounds of the formula A-9.

[0402] Specific compounds of this invention where R³ is hydrogen can beprepared as depicted in Chart B. Ethyl7-hydroxythieno[3,2-b]pyridine-6-carboxylate (A-3) prepared as describedin the literature (Elliott, R. L.; O'Hanlon, P. J.; Rogers, N. H.Tetrahedron 1987, 43, 3295-3302) is condensed with a benzylamine (e.g.4-chlorobenzylamine, 4-bromobenzylamine, or 4-fluorobenzylamine) at hightemperature, for example greater than about 50° C., to afford thecorresponding compounds of the general formula B-2. Alternatively, esterA-3 is saponified to afford the corresponding acid which is then coupledwith a benzylamine mediated by, for example 1,1′-carbonyldiimidazole orother suitable carboxylic acid activating agent, to likewise providecompounds of the general formula B-2. Amides of the formula B-2 can bealkylated at the ring nitrogen by treatment with an optionallysubstituted alkyl halide or alkyl mesylate in the presence of a base(e.g. potassium carbonate) or by reaction with an optionally substitutedalkanol under Mitsunobu conditions to afford compounds of the generalformula B-3 where R is a subset of R².

[0403] Iodination of thiophene A-3 with NIS and trifluoromethanesulfonicacid affords iodothiophene C-2. Condensation with a benzylamine (e.g.4-chlorobenzylamine, 4-bromobenzylamine, or 4-fluorobenzylamine) at hightemperature affords the corresponding amides of the general formula C-3.Amides of the formula C-3 are alkylated at the ring nitrogen bytreatment with an optionally substituted alkyl halide or alkyl mesylatein the presence of a base (e.g. potassium carbonate) or by reaction withan optionally substituted alkanol under Mitsunobu conditions to affordcompounds of the general formula C-4. Palladium catalyzed coupling ofC-4 with alkynes leads to compounds of formula C-5 wherein A is forexample R¹¹ as defined herein.

[0404] Amines of the formula D-3 can be prepared, for example, bybromination of ketones D-1 to form the corresponding bromoketones D-2,followed by reaction with a primary amine of the formula R⁷NH₂, forexample methylamine, and reduction with a suitable reducing agent, suchas sodium borohydride to afford compounds of the formula D-3 wherein Yis aryl or het.

[0405] An alternative preparation of alcohols of the forumla A-7 ispresented in Chart E. Aldehyde A-4 is reduced with sodium borohydride toafford alcohol E-1. Reaction with substituted benzylamines affordsamides of the formula E-2. N-Alkylation with optionally substitutedalkyl halides occurs in DMF in the presence of potassium carbonate toafford compounds of the formula A-7.

[0406] Amines of the formula F-6 can be prepared, for example, byconversion of ketones F-1 to enol silyl ethers of formula F-2 withtriisopropylsilyl triflate and diisopropylethylamine. Chlorination withN-chlorosuccinimide, followed by hydrolysis with aqueous HF then canafford alpha-chloroketones of formula F-4. Reduction of the ketones canbe accomplished with sodium borohydride and cerium trichloride toaffored racemic alcohols of the formula F-5. Alternatively, the ketonesF-4 can be reduced in an asymmetric fashion by, for example,hydrogenation with formic acid and the catalyst prepared from[RuCl₂(η⁶-p-cymene)]₂, Et₃N and (1R,2R)-N-p-toluenesulfonyl-1,2-diphenylethylenediamine to provide opticallyactive alcohols of the formula F-5. Reaction of alcohols F-5 withmethylamine then affords amines of formula F-6, wherein Y is aryl orhet.

[0407] The invention also provides processes and intermediates describedherein that are useful for preparing compounds of the invention. Forexample, compounds of the formula I wherein R² is other than H can beprepared from a corresponding compound of formula I wherein R² is H by,for example, alkylation. Accordingly, the present invention provides amethod for preparing compounds of the formula I wherein R² is other thanH, comprising alkylating a corresponding compound of the formula Iwherein R² is hydrogen with a compound of the formula R²-Z wherein Z isa suitable leaving group to provide the compound wherein R² is not H.Suitable Z leaving groups are known to those skilled in the art.

[0408] The invention also provides a method for preparing a compound offormula I:

[0409] wherein G and R² have the values described herein and R³ is ofthe formula —CH₂R^(a) where R^(a) is, for example, OR¹⁴, SR¹⁴, NR⁷R⁸,N-linked Het, or CN, comprising: reacting a corresponding nucleophilewith a compound of the formula III:

[0410] wherein X is a leaving group, for example, Cl, Br, alkyl ester,anhydride, tosyl, mesyl, or like groups, under conditions suitable toprovide the compound of formula I. Accordingly, the present inventionprovides a method for preparing compounds of the formula I wherein R³ isCH₂-Nu where Nu is a nucleophile.

[0411] The invention also provides processes and intermediates describedherein that are useful for preparing compounds of the invention. Forexample, the invention provides a method for preparing a compound offormula I wherein R² and R³ have the values described herein comprising:reacting a nucleophile, for example, of the formula NH₂—CH₂-G with acompound of the formula II

[0412] where X is a leaving group, for example, Cl, Br, alkyl ester,anhydride, tosyl, mesyl, or like groups, under conditions suitable toprovide the compound of formula I. Suitable conditions for preparing anamide from a corresponding carboxylic acid are well known in the art.The reaction can be carried out under any suitable conditions. Forexample, the reaction can conveniently be carried out by activating acarboxylic acid of the formula C(═O)—OH with a suitable activatingagent, and treating the activated acid of the formula C(═O)—X with, forexample, a substituted benzyl amine or like reactants, to provide thecompound of formula I. Suitable amines include, for example,4-chlorobenzylamine, 4-fluorobenzylamine, 4-bromobenzylamine,4-cyanobenzylamine, 4-nitrobenzylamine, and like amines. Accordingly,the present invention also provides intermediate compounds of theformula II wherein X is an activating leaving group.

[0413] The invention also provides a method for preparing a compound offormula A-4:

[0414] wherein R² is H, and X is a leaving group or blocking group,comprising: treating a compound of formula A-3:

[0415] wherein R³ is H, with a strong aprotic base and then reacting theresulting intermediate with a formylating agent.

[0416] In cases where compounds are sufficiently basic or acidic to formstable nontoxic acid or base salts, administration of the compounds assalts may be appropriate. Examples of pharmaceutically acceptable saltsare organic acid addition salts formed with acids which form aphysiological acceptable anion, for example, tosylate, methanesulfonate,acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts mayalso be formed, including hydrochloride, hydrobromide, sulfate, nitrate,bicarbonate, and carbonate salts.

[0417] Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example, by reacting asufficiently basic compound such as an amine with a suitable acidaffording a physiologically acceptable anion. Alkali metals, forexample, sodium, potassium or lithium, or alkaline earth metal salts,for example calcium, of carboxylic acids can also be made.

[0418] Compounds of the present invention can conveniently beadministered in a pharmaceutical composition containing the compound incombination with a suitable excipient, the composition being useful incombating viral infections. Pharmaceutical compositions containing acompound appropriate for antiviral use are prepared by methods andcontain excipients which are well known in the art. A generallyrecognized compendium of such methods and ingredients is Remington'sPharmaceutical Sciences by E. W. Martin (Mark Publ. Co., 15th Ed.,1975). The compounds and compositions of the present invention can beadministered parenterally, for example, by intravenous, intraperitonealor intramuscular injection, topically, orally, or rectally, depending onwhether the preparation is used to treat internal or external viralinfections.

[0419] For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparations shouldcontain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

[0420] The tablets, troches, pills, capsules, and the like may alsocontain the following: binders such as gum tragacanth, acacia, cornstarch or gelatin; excipients such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; a lubricant such as magnesium stearate; and a sweeteningagent such as sucrose, fructose, lactose or aspartame or a flavoringagent such as peppermint, oil of wintergreen, or cherry flavoring may beadded. When the unit dosage form is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier, such as avegetable oil or a polyethylene glycol. Various other materials may bepresent as coatings or to otherwise modify the physical form of thesolid unit dosage form. For instance, tablets, pills, or capsules may becoated with gelatin, wax, shellac or sugar and the like. A syrup orelixir may contain the active compound, sucrose or fructose as asweetening agent, methyl and propylparabens as preservatives, a dye andflavoring such as cherry or orange flavor. Of course, any material usedin preparing any unit dosage form should be pharmaceutically acceptableand substantially non-toxic in the amounts employed. In addition, theactive compound may be incorporated into sustained-release preparationsand devices.

[0421] The compounds or compositions can also be administeredintravenously or intraperitoneally by infusion or injection. Solutionsof the active compound or its salts can be prepared in water, optionallymixed with a nontoxic surfactant. Dispersions can also be prepared inglycerol, liquid polyethylene glycols, triacetin, and mixtures thereofand in oils. Under ordinary conditions of storage and use, thesepreparations contain a preservative to prevent the growth ofmicroorganisms.

[0422] Pharmaceutical dosage forms suitable for injection or infusioncan include sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

[0423] Sterile injectable solutions can be prepared by incorporating theactive compound in the required amount in the appropriate solvent withvarious of the other ingredients enumerated above, as required, followedby filter sterilization. In the case of sterile powders for thepreparation of sterile injectable solutions, the preferred methods ofpreparation are vacuum drying and the freeze drying techniques, whichyield a powder of the active ingredient plus any additional desiredingredient present in the previously sterile-filtered solutions.

[0424] For topical administration, the present compounds may be appliedin pure form, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

[0425] Useful solid carriers include finely divided solids such as talc,clay, microcrystalline cellulose, silica, alumina and the like. Usefulliquid carriers include water, alcohols or glycols orwater-alcohol/glycol blends, in which the present compounds can bedissolved or dispersed at effective levels, optionally with the aid ofnon-toxic surfactants. Adjuvants such as fragrances and additionalantimicrobial agents can be added to optimize the properties for a givenuse. The resultant liquid compositions can be applied from absorbentpads, used to impregnate bandages and other dressings, or sprayed ontothe affected area using pump-type or aerosol sprayers. Thickeners suchas synthetic polymers, fatty acids, fatty acid salts and esters, fattyalcohols, modified celluloses or modified mineral materials can also beemployed with liquid carriers to form spreadable pastes, gels,ointments, soaps, and the like, for application directly to the skin ofthe user.

[0426] Examples of useful dermatological compositions which can be usedto deliver the compounds of formula I to the skin are known to the art;for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S.Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman(U.S. Pat. No. 4,820,508).

[0427] Useful dosages of the compounds of formula I can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949.

[0428] The compound is conveniently administered in unit dosage form;for example, containing 5 to 1,000 mg, conveniently 10 to 750 mg, mostconveniently, 50 to 500 mg of active ingredient per unit dosage form.The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

[0429] For internal infections, the compositions can be administeredorally or parenterally at dose levels, calculated as the free base, ofabout 0.1 to 300 mg/kg, preferably 1.0 to 30 mg/kg of mammal bodyweight, and can be used in man in a unit dosage form, administered oneto four times daily in the amount of 1 to 1,000 mg per unit dose.

[0430] For parenteral administration or for administration as drops, asfor eye infections, the compounds are presented in aqueous solution in aconcentration of from about 0.1 to about 10%, more preferably about 0.1to about 7%. The solution may contain other ingredients, such asemulsifiers, antioxidants or buffers.

[0431] Generally, the concentration of the compound(s) of formula I in aliquid composition, such as a lotion, will be from about 0.1-25 wt-%,preferably from about 0.5-10 weight percent. The concentration in asemi-solid or solid composition such as a gel or a powder will be about0.1-5 weight percent, preferably about 0.5-2.5 weight percent.

[0432] The exact regimen for administration of the compounds andcompositions disclosed herein will necessarily be dependent upon theneeds of the individual subject being treated, the type of treatmentand, of course, the judgment of the attending practitioner.

[0433] The antiviral activity of a compound of the invention can bedetermined using pharmacological models which are well known to the art,or using Test A described below.

[0434] The compounds of formula (I) and pharmaceutically acceptablesalts thereof are useful as antiviral agents. Thus, they are useful tocombat viral infections in animals, including man. The compounds aregenerally active against herpes viruses, and are particularly usefulagainst the varicella zoster virus, the Epstein-Barr virus, the herpessimplex virus, the human herpes virus type 8 (HHV-8) and thecytomegalovirus (CMV). The compounds of the present invention may alsobe useful for the treatment of herpesvirus infections in animals, forexample, illnesses caused by bovine herpesvirus 1-5 (BHV), ovineherpesvirus 1 and 2, Canine herpesvirus 1, equine herpesvirus 1-8 (EHV),feline herpesvirus 1 (FHV), and pseudorabies virus (PRV).

[0435] The compounds of the present invention may also useful for thetreatment of several cardiovascular diseases such as atherosclerosis andrestenosis. These diseases have been connected with inflammation ofcoronary vessel walls resulting from infection or reactivation ofherpesviruses.

[0436] While many of the compounds of the present invention have shownactivity against the CMV polymerase, these compounds may be activeagainst the cytomegalovirus by this or other mechanisms of action. Thus,the description below of these compounds' activity against the CMVpolymerase is not meant to limit the present invention to a specificmechanism of action.

[0437] Test A.

[0438] The HCMV polymerase assay is performed using a scintillationproximity assay (SPA) as described in several references, such as N. D.Cook, et al., Pharmaceutical Manufacturing International, pages 49-53(1992); K. Takeuchi, Laboratory Practice, September issue (1992); U.S.Pat. No. 4,568,649 (1986); which are incorporated by reference herein.Reactions are performed in 96-well plates. The assay is conducted in 100μl volume with 5.4 mM HEPES (pH 7.5), 11.7 mM KCl, 4.5 mM MgCl₂, 0.36mg/mL BSA, and 90 nM ³H-dTTP. Assays are run with and without CHAPS,(3-[(3-cholamidopropyl)-dimethyl-ammonio]-1-propane-sulfonate) at afinal concentration of 2 mM. HCMV polymerase is diluted in enzymedilution buffer containing 50% glycerol, 250 mM NaCl, 10 mM HEPES (pH7.5), 100 μg/mL BSA, and 0.01% sodium azide. The HCMV polymerase, whichis expressed in recombinant baculovirus-infected SF-9 cells and purifiedaccording to literature procedures, is added at 10% (or 10 μl) of thefinal reaction volume, i.e., 100 μl. Compounds are diluted in 50% DMSOand 10 μl are added to each well. Control wells contain an equivalentconcentration of DMSO. Unless noted otherwise, reactions are initiatedvia the addition of 6 nM biotinylated poly(dA)-oligo(dT) template/primerto reaction mixtures containing the enzyme, substrate, and compounds ofinterest. Plates are incubated in a 25° C. or 37° C. H₂O bath andterminated via the addition of 40 μL/reaction of 0.5 M EDTA (pH 8) perwell. Reactions are terminated within the time-frame during whichsubstrate incorporation is linear and varied depending upon the enzymeand conditions used, i.e., 30 min. for HCMV polymerase. Ten μl ofstreptavidin-SPA beads (20 mg/mL in PBS/10% glycerol) are addedfollowing termination of the reaction. Plates are incubated 10 min. at37° C., then equilibrated to room temperature, and counted on a PackardTopcount. Linear regressions are performed and IC₅₀'s are calculatedusing computer software.

[0439] A modified version of the above HCMV polymerase assay isperformed as described above, but with the following changes: Compoundsare diluted in 100% DMSO until final dilution into assay buffer. In theprevious assay, compounds are diluted in 50% DMSO. 4.5 mM dithiotherotol(DTT) is added to the polymerase buffer. Also, a different lot of CMVpolymerase is used, which appears to be more active resulting in a morerapid polymerase reaction. Representative compounds of formula I thatwere tested were found to be active in this assay.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Example 1N-(4-Chlorobenzyl)-7-hydroxythieno[3,2-b]pyridine-6-carboxamide

[0440]

[0441] A mixture of ethyl 7-hydroxythieno[3,2-b]pyridine-6-carboxylate(223 mg) prepared as described in the literature (Elliott, R. L.;O'Hanlon, P. J.; Rogers, N. H. Tetrahedron 1987, 43, 3295-3302) and4-chlorobenzylamine (1.2 mL) was heated to 190° C. for 1 h. The crudeproduct was purified by column chromatography (CH₂Cl₂/methanol, 100/1;50/1; 33/1) and the resulting solid was recrystallized from glacialacetic acid/water to afford 84 mg of the title compound as a tan solid.

[0442] Physical characteristics follow:

[0443] Mp 295° C. dec; ¹H NMR (300 MHz, DMSO-d₆) δ 13.15, 10.44, 8.69,8.13, 7.42-7.33, 4.54; ¹³C NMR (75 MHz, CF₃CO₂D) δ 160.7, 158.2, 138.5,133.0, 130.7, 125.6, 124.3, 119.9, 116.9, 109.3, 97.1, 34.8; MS (ESI−)m/z 317 (M-H)³¹. Anal. Found: C, 56.22; H, 3.43; N, 8.71; Cl, 10.80; S,10.09.

Example 2N-(4-Chlorobenzyl)-4-ethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide

[0444]

[0445] N-(4-chlorobenzyl)-7-hydroxythieno[3,2-b]pyridine-6-carboxamide(Example 1, 885 mg)was dissolved in DMF (20 mL) and to the solution wasadded potassium carbonate (1.92 g) and iodoethane (1.1 mL). The mixturewas heated to 100° C. for 16 h. After cooling to room temperature, thereaction mixture was poured into water (100 mL) and extracted with EtOAc(3×100 mL). The combined organic layers were washed with water (3×25 mL)followed by brine (25 mL), dried (MgSO₄), and concentrated. The crudeproduct was purified by column chromatography (EtOAc/heptane, 1/1;CH₂Cl₂/methanol, 100/1) and the resulting solid was recrystallized fromethanol to afford 590 mg of the title compound as a white solid.

[0446] Physical characteristics are as follows:

[0447] Mp 189-192° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 10.42, 8.76, 8.22,7.65, 7.41-7.33, 4.54, 4.46, 1.39; ¹³C NMR (75 MHz, DMSO-d₆) δ 172.1,164.8, 145.6, 144.7, 139.0, 135.5, 131.9, 131.1, 129.6, 128.8, 118.6,112.7, 50.2, 41.9, 15.7; MS (EI) m/z 346 (M+). Anal. Found: C, 58.68; H,4.47; N, 8.09; Cl, 10.26; S, 9.34.

[0448] PREPARATION 1. Ethyl7-hydroxy-2-iodothieno[3,2-b]pyridine-6-carboxylate

[0449] To a stirring solution of ethyl7-hydroxythieno[3,2-b]pyridine-6-carboxylate (Elliot, R. L, O'Hanlon, P.J., Rogers, N. H. Tetrahedron 43 (14) 3295-3302 (1987)) (2.50 g, 10.96mmol) in trifluomethanesulfonic acid (50 mL) at 0° C. was added N-iodosuccinimide (2.46 g, 10.96 mmol) portion wise. The mixture was stirredfor 1 hour, allowing the solution to warm to ambient temperature. Ice(50 g) was added and the resulting aqueous extracted with CH₂Cl₂ (3×100mL). The organic layers were combined, dried over MgSO₄ and solventremoved to afford 2.92 g title compound as a white solid.

[0450] Physical characteristics are as follows:

[0451] MS (EI) m/z (rel. intensity) 349 (M⁺, 0), 349 (98), 304 (17), 303(99), 176 (18), 108 (27), 86 (13), 84 (17), 81 (23), 69 (22), 53 (21).

[0452] PREPARATION 2. N-(4-chlorobenzyl)-7-hydroxy-2-iodothieno[3,2-b]pyridine-6-carboxamide.

[0453] A stirring mixture of ethyl7-hydroxy-2-iodothieno[3,2-b]pyridine-6-carboxylate (1.5 g, 4.29 mmol)in 4-chlorobenzylamine (15 mL) was heated at 190° C. for 1 hour. Theresulting dark solution was cooled to ambient temperature and 100 mLtoluene added. The resulting solid was collected by filtration and driedat 50° C. for 16 h to afford 0.875 g title compound as a yellow solid.

[0454] Physical characteristics are as follows:

[0455] MS (EI) m/z (rel. intensity) 444 (M⁺, 0), 277 (37), 142 (27), 140(99), 128 (21), 127 (54), 125 (88), 106 (23), 89 (20), 77 (27), 50 (21).Anal. Found: C, 40.76; H, 2.59; N, 6.35. The title compound is also acompound of formula I.

[0456] PREPARATION 3.N-(4-chlorobenzyl)-2-iodo-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0457] To a stirring mixture ofN-(4-chlorobenzyl)-7-hydroxy-2-iodothieno[3,2-b]pyridine-6-carboxamide(0.50 g, 1.12 mmol) in DMF (20 mL) in a pressure tube was added K₂CO₃(0.31 g, 2.25 mmol). To the resulting suspension was added CH₃I (0.335g,2.36 mmol), the vessel capped and heated at 90° C. for 16 h. Theresulting dark suspension was cooled to ambient temperature and pouredinto H₂O (100 mL). The aqueous solution was extracted with CH₂Cl₂ (3×100mL). The organic layers were combined, dried over MgSO₄ and solventremoved to afford 0.38 g title compound as a yellow solid.

[0458] Physical characteristics are as follows:

[0459] MS (EI) m/z (rel. intensity) 458 (M⁺, 0), 458 (24), 291 (99), 192(19), 165 (41), 140 (31), 138 (19), 137 (20), 136 (22), 128 (22), 127(21). Anal. Found: C, 42.03; H, 2.74; N, 6.08. The title compound isalso a compound of formula I.

Example 3N-(4-chlorobenzyl)-2-(3-hydroxyprop-1-ynyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0460]

[0461] A mixture ofN-(4-chlorobenzyl)-2-iodo-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(0.20 g, 0.44 mmol), Pd(PhCN)₂Cl₂ (10 mg) CuI (7 mg) Et₃N (1 mL) andpropargyl alcohol (0.036 g, 0.66 mmol) in DMF was stirred at ambienttemperature overnight. The solvent was removed and the residuepartitioned between H₂O and CH₂Cl₂ (100 mL each). The layers wereshaken, the organic layer separated and dried over MgSO₄. The solventswere removed in vacuo and the residue purified via flash columnchromatography (eluant 5% MeOH/CH₂Cl₂) to afford 0.117 g title compoundas a white solid.

[0462] Physical characteristics are as follows:

[0463] MS (EI) m/z (rel. intensity) 386 (M⁺, 0), 219 (38), 86 (61), 84(66), 78 (96), 65 (40), 64 (36), 63 (99), 62 (35), 61 (56), 51 (59).Anal. Calcd for C₁₉H₁₅ClN₂O₃S(1.1 H₂O). Found: C, 56.11; H, 3.90; N,6.91.

[0464] PREPARATION 4. Diethyl 2-{[(thien-3-yl)amino]methylene}malonate.

[0465] To a solution of methyl 3-amino-2-thiophenecarboxylate (Aldrich23,290-4, 31.4 g, 0.20 mol) in 95% ethanol (180 mL) was added 1.0 N NaOH(240 mL). The mixture was heated to reflux and stirred for 1 hr. Theresulting solution was cooled to room temperature before the addition ofglacial acetic acid (13.8 mL, 0.24 mol). After stirring for 1.5 hrs atroom temperature, diethyl ethoxymethylenemalonate (DEEM, 40.8 mL, 0.202mol) was added. The mixture was stirred vigorously for 1 hr, and then itwas left standing at room temp for 3 hours and filtered. The solid wascollected and dried in a vacuum oven overnight at room temperature,affording a white solid (43.3 g).

[0466] Physical characteristics are as follows:

[0467]¹H NMR (DMSO-d₆) δ 10.78 (1 H), 8.29 (1 H), 7.58 (1 H), 7.39 (1H), 7.28 (1 H), 4.15 (4 H), 1.24 (6 H); HPLC retention time (Conditions:Instrument: Hewlett Packard HP1100; Column: Zorbax SB-C18 (4.6×75 mm,3.5 micron); Detector: UV Ε 210 nm, 254 nm; Flow Rate: 2.0 mL/min;Gradient: 10:90 to 90:10 acetonitrile: 0.07% aq. H₃PO₄ over 4.5 minutes;then 90:10 acetonitrile:0.07% aq. H₃PO₄ for 1.5 minutes)=3.80 min; MS(ESI+) for C₁₂H₁₅NO₄S m/z 270 (M+H)⁺.

[0468] PREPARATION 5. Ethyl7-hydroxythieno[3,2-b]pyridine-6-carboxylate.

[0469] A solution of diethyl 2-{[(thien-3-yl)amino]methylene}malonate(43.4 g, 0.16 mol) in diphenyl ether (200 mL) in a 500 mL round bottom(RB) flask was degassed by three cycles of evacuation and nitrogenpurge. The solution was then heated rapidly with a heating mantle toreflux and stirred at that temperature for 50 minutes. The heatingmantle was removed and the yellow to brown solution was then stirred for3 hours and was allowed to stand at room temperature for 16 hours,during which time a copious ppt appeared. The mixture was diluted withdiethyl ether (300 mL) before collecting the solid by vacuum filtration.The collected solid was washed thoroughly with ether and dried in vacuo,leaving a white solid (21 g). More solid precipitated after the filtratestanding at room temperature overnight (7 g).

[0470] Physical characteristics are as follows:

[0471]¹H NMR (400 MHz, DMSO-d₆) δ 12.76 (1 H), 8.5 (1 H), 8.04 (1 H),7.30 (1 H), 4.20 (2 H), 1.28 (3 H); HPLC ret time=0.572 min; MS (ESI+)for C₁₀H₉NO₃S m/z 224 (M+H)⁺.

[0472] PREPARATION 6. Ethyl2-formyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate.

[0473] A fresh solution of LDA was prepared by adding n-BuLi (2.5 M inhexanes, 36 mL, 89 mmol) to a 0° C. solution of diisopropylamine (15 mL,110 mmol) in anhyd. THF (100 mL). The LDA solution was then added via aneedle cannula dropwise to a suspension of ethyl7-hydroxythieno[3,2-b]pyridine-6-carboxylate (5.00 g, 22 mmol) in THF(200 mL) at −78° C. over a period of about 1 hr. After addition of theLDA, the solution was stirred at −78° C. for 1 hr before the dropwiseaddition of dry DMF (9 mL, 110 mmol). The reaction was stirred at −78°C. for 30 minutes and then the dry ice bath was removed. The temperaturewas allowed to rise to over 0° C. before the reaction was quenched bythe addition of sat. aq. ammonium chloride (100 mL) and ice (50 g).Water (150 mL) was added, and the mixture was stirred vigorously for 30minutes. The solid ppt was collected by vacuum filtration, and the solidwas washed with water. Drying in vacuo left a yellow solid (5.22 g).

[0474] Physical characteristics are as follows:

[0475]¹H NMR (400 MHz, DMSO-d₆) δ 10.07 (1 H), 8.68 (1 H), 8.16 (1 H),4.23 (2 H), 1.30 (3 H); HPLC ret time=1.709 min; MS (ESI+) for C₁₁H₉NO₄Sm/z 252 (M+H)⁺.

[0476] PREPARATION 7. Ethyl2-formyl-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate.

[0477] Methyl iodide (1.2 mL, 19.3 mmol) was added to a mixture of ethyl2-formyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate (3.0 g,11.9 mmol), potassium carbonate (2.5 g, 18.1 mmol) in DMF (30 mL) at 0°C. After the addition of methyl iodide, the mixture was stirred at roomtemperature for 1 hr. The mixture was diluted with water (40 mL),stirred at room temperature for 15 minutes, and then filtered. Thecollected solid was washed with water and dried in vacuo, leaving asolid (1.3 g, 41%). The aqueous phase was extracted with methylenechloride (2×50 mL). The organic layers were combined, washed with water(50 mL) and brine (50 mL), and dried over magnesium sulfate. Removal ofthe solvent gave a second crop of product (0.34 g).

[0478] Physical characteristics are as follows:

[0479]¹H NMR (400 MHz, DMSO-d₆) δ 10.10 (1 H), 8.66 (1 H), 8.43 (1 H),4.24 (2 H), 4.00 (3 H), 1.28 (3 H); ¹³C NMR (DMSO-d6) δ 185.54, 169.32,164.14, 148.79, 145.47, 143.65, 135.80, 127.57, 111.74, 59.96, 41.25,14.18; HPLC ret time=1.827 min; MS (ESI+) for C₁₂H₁₁NO₄S m/z 266 (M+H)⁺.

[0480] PREPARATION 8. Ethyl2-(hydroxymethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate.

[0481] To a solution of ethyl2-formyl-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate(1.0 g, 3.8 mmol) in 1,2-dichloroethane (23 mL) was added sodiumtriacetoxyborohydride (1.6 g, 7.5 mmol). The reaction was stirred atroom temperature for 24 hours. The reaction was poured into sat. aq.sodium bicarbonate (50 mL) and methylene chloride (30 mL), before it wasquenched with water (50 mL). The mixture was allowed to stand at 0° C.overnight. The solid ppt. was collected by vacuum filtration and washedwith water. Drying in vacuo yielded an off-white solid (0.36 g, 36%).The filtrate was concentrated to near dryness and diluted with water (20mL). Filtration followed by treatment with high vacuum gave a secondcrop of product (0.45 g).

[0482] Physical characteristics are as follows:

[0483]¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (1 H), 7.32 (1 H), 5.88 (1 H),4.74 (2 H), 4.21 (2 H), 3.90 (3 H), 1.27 (3 H); HPLC ret time=1.522 min;MS (ESI+) for C₁₂H₁₃NO₄S m/z 268 (M+H)⁺.

Example 4N-(4-chlorobenzyl)-2-(hydroxymethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide

[0484]

[0485] Ethyl2-(hydroxymethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate(250 mg, 0.94 mmol) was suspended in 4-chlorobenzylamine (2.0 mL, 16.4mmol). The mixture was stirred at 80° C. for 16 hours before it wasquenched with a mixture of 1.0 M hydrochloric acid (25 mL) and ice (5g). The mixture was stirred at room temperature for 1 hr. The solid ppt.was collected by vacuum filtration and washed thoroughly with 50 mL ofwater. Drying in vacuo left a white solid (0.26 g).

[0486] Physical characteristics are as follows:

[0487]¹H NMR (400 MHz, DMSO-d₆) δ 10.46 (1 H), 8.68 (1 H), 7.40, 7.37 (4H), 5.94 (1 H), 4.78 (2 H), 4.54 (2 H), 3.99 (3 H); HPLC ret time=2.763min; MS (ESI+) for C₁₇H₁₅ClN₂O₃S m/z 363 (M+H)⁺.

[0488] PREPARATION 9.N-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0489] Methanesulfonyl chloride (0.22 mL , 2.8 mmol) was added to amixture of ethyl2-(hydroxymethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate(400 mg, 1.1 mmol), collidine (0.37 mL, 2.8 mmol) and DMAP (67 mg, 0.55mmol) in DMF (20 mL). The reaction was stirred at room temperature for 2hours, going to an orange/amber solution. The reaction mixture waspoured into ice water (40 mL of water +50 g of ice) and stirred for 10minutes. The solid ppt was collected by filtration, washed with waterand dried in vacuo, leaving the title compound as a white solid (0.36g).

[0490] Physical characteristics are as follows: ¹H NMR (400 MHz,DMSO-d₆) δ 10.3 (1 H), 8.72 (1 H), 7.40, 7.37 (4 H), 5.16 (2 H), 4.54 (2H), 4.01 (3 H); HPLC ret time=3.66 min; MS (ESI+) for C₁₇H₁₄Cl₂N₂O₂S m/z381 (M+H)⁺. The title compound is also a compound of formula I.

Example 5N-(4-chlorobenzyl)-4-methyl-2-(morpholin-4-ylmethyl)-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0491]

[0492] A mixture ofN-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(50 mg, 0.13 mmol), morpholine (17.4 mg, 0.20 mmol) anddiisopropylethylamine (35 μL, 0.20 mmol) in dry DMF (2.7 mL) was heatedto 60° C., becoming a solution. The reaction was stirred for 3 hours atthat temperature. After cooling to room temperature, the solution wasdiluted with water (5 mL). The resulting milky suspension was stirredvigorously for 30 minutes, and then left standing overnight at roomtemp. The mixture was filtered, and the collected solid was washed withwater and dried in vacuo, leaving a white solid. Recrystallization fromacetonitrile (10 mL) gave the title compound (48 mg) as a flocculentwhite solid.

[0493] Physical characteristics are as follows: ¹H NMR (400 MHz,DMSO-d₆) δ 10.46 (1 H), 8.67 (1 H), 7.47 (1 H), 7.34 (4 H), 4.54 (2 H),3.99 (3 H), 3.81 (2 H), 3.61 (4 H), 2.47 (4 H); HPLC ret time=2.224 min;Anal. Found: C, 58.35; H, 5.15; N, 9.37; MS (ESI+) m/z 432 (M+H)⁺.

Example 6N-(4-chlorobenzyl)-2-{[[2-hydroxy-2-(3-methoxyphenyl)ethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0494]

[0495] A mixture ofN-(4-chlorobenzyl)-2-(chloromethyl)-4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(50 mg, 0.13 mmol), 1-(3-methoxyphenyl)-2-(methylamino)ethanol(Chem.Abstr.; 1957; 6548) (36 mg, 0.20 mmol) and diisopropylethylamine(35 μL, 0.20 mmol) in dry DMF (2.7 mL) was heated to 60° C., becoming asolution. The reaction was stirred for 3 hours at that temperature.After cooling to room temperature, the solution was diluted with water(5 mL). The resulting milky suspension was stirred vigorously for 30minutes, and then left standing overnight at room temp. The mixture wasfiltered, and the collected solid was washed with water and dried invacuo, leaving a white solid. Recrystallization from acetonitrile (10mL) gave the title compound (47 mg) as a white solid.

[0496] Physical characteristics are as follows: HPLC ret time=2.639 min;MS (ESI+) m/z 526 (M+H)⁺.

[0497] PREPARATION 10. 2-bromo-1-(2-furyl)ethanone.

[0498] Bromine (6.5 mL, 127 mmol) was added dropwise over 1 hour to asolution of 2-acetylfuran (11.0 g, 100 mmol) in dioxane/Et₂O (1/2, 60mL) at 0C. After addition was complete, the reaction was warmed to roomtemperature and stirred for 2 hours. A saturated ammonium chloridesolution (70 mL) was then added. The organic layer was removed and theaqueous layer was extracted with Et₂O (2×50 mL). The combined organiclayers were dried over MgSO₄, filtered, and concentrated. The resultingbrown solid was purified using a Biotage 40 M column (hexanes/CH₂Cl₂,70/30) to yield the bromoketone as a yellow oil that solidified uponstanding (4.40 g).

[0499] Physical characteristics are as follows:

[0500]¹H NMR (DMSO-d₆) δ 4.66 (2 H), 6.78 (1 H), 7.66 (1 H), 8.09 (1 H).

[0501] PREPARATION 11. 1-(2-furyl)-2-(methylamino)ethanol.

[0502] A solution of 2-bromo-1-(2-furyl)ethanone (3.0 g, 15.88 mmol) inmethanol (16 mL) was added dropwise to a 2.0 M solution of methylaminein methanol (79.4 mL, 158.8 mmol) at 0° C. The reaction stirred at 0° C.for 30 minutes. A solution of sodium borohydride (0.90 g, 23.82 mmol) inH₂O (16 mL) was then added dropwise. The reaction mixture was stirred at0° C. for 30 minutes and then quenched with 2 N HCl (to pH 3-4). Thereaction mixture was concentrated in vacuo to remove methanol and thenpoured into a cold mixture of EtOAc (80 mL) and 2 N HCl (40 mL). Theorganic layer was removed. The aqueous layer was adjusted to pH 12 with2 N NaOH and extracted with EtOAc (3×80 mL). The combined extracts weredried over MgSO₄, filtered, and concentrated in vacuo. The resultingbrown oil was purified using a Biotage 40 M column (CHCl₃/methanol,95/5; CHCl₃/methanol/NH4OH, 90/10/1) to yield the aminoalcohol as abrown oil (0.86 g).

[0503] Physical characteristics are as follows:

[0504]¹H NMR (DMSO-d₆) δ 2.33 (3 H), 2.77-2.66 (2 H), 4.61 (1 H), 6.26(1 H), 6.38 (1 H), 7.56 (1 H). OAMS (ES+) m/z 141.9 (M+H)⁺.

Example 7N-(4-chlorobenzyl)-2-{[[2-(2-furyl)-2-hydroxyethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0505]

[0506] A mixture ofN-(4-chlorobenzyl)-2-(chloromethyl)-4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(50 mg, 0.13 mmol), 1-(2-furyl)-2-(methylamino)ethanol (Preparation 11)(28 mg, 0.20 mmol) and diisopropylethylamine (35 μL, 0.20 mmol) in dryDMF (2.7 mL) was heated to 60° C., becoming a solution. The reaction wasstirred for 3 hours at that temperature. After cooling to roomtemperature, the solution was diluted with water (5 mL). The resultingmilky suspension was stirred vigorously for 30 minutes, and then leftstanding overnight at room temp. The mixture was filtered, and thecollected solid was washed with water and dried in vacuo, leaving awhite solid. Recrystallization from acetonitrile (10 mL) gave the titlecompound (49 mg) as a white solid.

[0507] Physical characteristics are as follows: HPLC ret time=2.414 min;Anal. Found: C, 56.23; H, 4.82; N, 8.11; MS (ESI−) m/z 484 (M-H)⁺.

Example 8N-(4-chlorobenzyl)-2-{[(2-hydroxy-2-phenylethyl)(methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0508]

[0509] A mixture ofN-(4-chlorobenzyl)-2-(chloromethyl)-4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(50 mg, 0.13 mmol), 2-(methylamino)-1-phenylethanol (Aldrich, 30 mg,0.20 mmol) and diisopropylethylamine (35 μL, 0.20 mmol) in dry DMF (2.7mL) was heated to 60° C., becoming a solution. The reaction was stirredfor 3 hours at that temperature. After cooling to room temperature, thesolution was diluted with water (5 mL). The resulting milky suspensionwas stirred vigorously for 30 minutes, and then left standing overnightat room temp. The mixture was filtered, and the collected solid waswashed with water and dried in vacuo, leaving a white solid.Recrystallization from acetonitrile (10 mL) gave the title compound (47mg) as a white solid.

[0510] Physical characteristics are as follows: HPLC ret time=2.595 min;Anal. Found: C, 59.15; H, 5.26; N, 7.96; MS (ESI+) m/z 496 (M+H)⁺.

Example 9N-(4-chlorobenzyl)-2-{[[2-hydroxy-2-(1,3-thiazol-2-yl)ethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0511]

[0512] A mixture ofN-(4-chlorobenzyl)-2-(chloromethyl)-4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(50 mg, 0.13 mmol), 2-(methylamino)-1-(1,3-thiazol-2-yl)ethanol(prepared from 2-acetyl-1,3-thiazole by the procedure outlined inPreparation 10 and 11)(31 mg, 0.20 mmol) and diisopropylethylamine (35μL, 0.20 mmol) in dry DMF (2.7 mL) was heated to 60° C., becoming asolution. The reaction was stirred for 3 hours at that temperature.After cooling to room temperature, the solution was diluted with water(5 mL). The resulting milky suspension was stirred vigorously for 30minutes, and then left standing overnight at room temp. The mixture wasfiltered, and the collected solid was washed with water and dried invacuo, leaving a white solid. Recrystallization from acetonitrile (10mL) gave the title compound (39 mg) as a flocculent white solid.

[0513] Physical characteristics are as follows: HPLC ret time=2.357 min;Anal. Found: C, 53.82; H, 4.62; N, 10.72; MS (ESI+) m/z 503 (M+H)⁺.

Example 10N-(4-chlorobenzyl)-2-{[{2-hydroxy-2-[4-(methylsulfonyl)phenyl]ethyl}(methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0514]

[0515] A mixture ofN-(4-chlorobenzyl)-2-(chloromethyl)-4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(50 mg, 0.13 mmol), 2-(methylamino)-1-[4-(methylsulfonyl)phenyl]ethanol(prepared from 4-methylsulphonylacetophenone by the procedure outlinedin Preparation 10 and 11)(46 mg, 0.20 mmol) and diisopropylethylamine(35 μL, 0.20 mmol) in dry DMF (2.7 mL) was heated to 60° C., becoming asolution. The reaction was stirred for 4 hours at that temperature.After cooling to room temperature, the solution was diluted with water(5 mL). The resulting milky suspension was stirred vigorously for 30minutes, and then left standing overnight at room temp. The mixture wasfiltered, and the collected solid was washed with water and dried invacuo, leaving a white solid. Recrystallization from acetonitrile (10mL) gave the title compound (54 mg) as a flocculent white solid.

[0516] Physical characteristics are as follows: HPLC ret time=2.416 min;MS (ESI+) m/z 574 (M+H)⁺.

Example 11N-(4-chlorobenzyl)-2-{[(2-hydroxy-2-pyridin-2-ylethyl)(methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0517]

[0518] A mixture ofN-(4-chlorobenzyl)-2-(chloromethyl)-4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(50 mg, 0.13 mmol), 2-(methylamino)-1-pyridin-2-ylethanol (prepared from2-acetylpyridine by the procedure outlined in Preparation 10 and 11)(31mg, 0.20 mmol) and diisopropylethylamine (35 μL, 0.20 mmol) in dry DMF(2.7 mL) was heated to 60° C., becoming a solution. The reaction wasstirred for 4 hours at that temperature. After cooling to roomtemperature, the solution was diluted with water (5 mL). The resultingmilky suspension was stirred vigorously for 30 minutes, and then leftstanding overnight at room temp. The mixture was filtered, and thecollected solid was washed with water and dried in vacuo, leaving awhite solid. Recrystallization from acetonitrile (10 mL) gave the titlecompound (45 mg) as a flocculent white solid.

[0519] Physical characteristics are as follows: HPLC ret time=2.228 min;MS (ESI+) m/z 519 (M+Na)⁺.

Example 12N-(4-chlorobenzyl)-2-{[(2-hydroxy-2-pyrazin-2-ylethyl)(methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0520]

[0521] A mixture ofN-(4-chlorobenzyl)-2-(chloromethyl)-4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(50 mg, 0.13 mmol), 2-(methylamino)-1-pyrazin-2-ylethanol (prepared from2-acetylpyrazine by the procedure outlined in Preparations 10 and11)(0.20 mmol) and diisopropylethylamine (35 μL, 0.20 mmol) in dry DMF(2.7 mL) was heated to 60° C., becoming a solution. The reaction wasstirred for 4 hours at that temperature. After cooling to roomtemperature, the solution was diluted with water (5 mL). The resultingmilky suspension was stirred vigorously for 30 minutes, and then leftstanding overnight at room temp. The mixture was filtered, and thecollected solid was washed with water and dried in vacuo, leaving awhite solid. Recrystallization from acetonitrile (10 mL) gave the titlecompound (23 mg).

[0522] Physical characteristics are as follows:

[0523] HPLC ret time=2.21 min; MS (ESI+) m/z 498 (M+H)⁺.

Example 13N-(4-chlorobenzyl)-2-{[[2-(5-cyanothien-2-yl)-2-hydroxyethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0524]

[0525] A mixture ofN-(4-chlorobenzyl)-2-(chloromethyl)-4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(50 mg, 0.13 mmol),5-[1-hydroxy-2-(methylamino)ethyl]thiophene-2-carbonitrile (preparedfrom 5-acetylthiophene-2-carbonitrile by the procedure outlined inPreparations 10 and 11)(0.20 mmol) and diisopropylethylamine (35 μL,0.20 mmol) in dry DMF (2.7 mL) was heated to 60° C., becoming asolution. The reaction was stirred for 4 hours at that temperature.After cooling to room temperature, the solution was diluted with water(5 mL). The resulting milky suspension was stirred vigorously for 30minutes, and then left standing overnight at room temp. The mixture wasfiltered, and the collected solid was washed with water and dried invacuo, leaving a white solid. Recrystallization from acetonitrile (10mL) gave the title compound (37 mg).

[0526] Physical characteristics are as follows:

[0527] HPLC ret time=2.60 min; MS (ESI+) m/z 527 (M+H)⁺.

Example 14N-(4-chlorobenzyl)-2-{[[2-hydroxy-2-(4-hydroxyphenyl)ethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0528]

[0529] A mixture ofN-(4-chlorobenzyl)-2-(chloromethyl)-4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(50 mg, 0.13 mmol), synephrine (0.20 mmol) and diisopropylethylamine (35μL, 0.20 mmol) in dry DMF (2.7 mL) was heated to 60° C., becoming asolution. The reaction was stirred for 4 hours at that temperature.After cooling to room temperature, the solution was diluted with water(5 mL). The resulting milky suspension was stirred vigorously for 30minutes, and then left standing overnight at room temp. The mixture wasfiltered, and the collected solid was washed with water and dried invacuo, leaving a white solid. Recrystallization from acetonitrile (10mL) gave the title compound (38 mg).

[0530] Physical characteristics are as follows:

[0531] HPLC ret time=2.34 min; MS (ESI+) m/z 512 (M+H)⁺.

[0532] PREPARATION 12. Ethyl2-(hydroxymethyl)-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate.

[0533] To a 0° C. mixture of ethyl2-formyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate(Preparation 6, 0.628 g, 2.5 mmol) and acetic acid (0.71 mL, 12.5 mmol)in 1,2-dichloroethane (23 mL) was added sodium triacetoxyborohydride(1.06 g, 5.0 mmol). The mixture was stirred at 0° C. for 5 minutes andat room temperature for 24 hrs. A saturated solution of sodiumbicarbonate (25 mL) and methylene chloride (25 mL) were added. Afterstirring vigorously for 5 minutes, the mixture was filtered. Thecollected solid was washed with water and methylene chloride, then driedin vacuo, leaving the title compound as a pale yellow solid (0.486 g).

[0534] Physical characteristics are as follows:

[0535]¹H NMR (400 MHz, DMSO-d₆) δ 12.6 (1H), 8.44 (1 H), 7.13 (1 H),5.19 (1H), 4.71 (2H), 4.20 (2H), 1.27 (3H); HPLC ret time=1.39 min; MS(ESI−) for C₁₁H₁₁NO₄S m/z 252 (M−H)⁻.

[0536] PREPARATION 13.N-(4-chlorobenzyl)-2-(hydroxymethyl)-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0537] A mixture of ethyl2-(hydroxymethyl)-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate(1.40 g, 5.53 mmol) in 4-chlorobenzylamine (13.5 mL, 111 mmol) undernitrogen was heated at 80° C. for 5 hrs. The reaction was cooled to roomtemperature before the addition of 1 N HCl (120 mL). The resulting paleyellow precipitate was collected by filtration and washed thoroughlywith 1 N HCl, then water. Drying in vacuo left the title compound as apale yellow solid (1.85 g).

[0538] Physical characteristics are as follows:

[0539]¹H NMR (400 MHz, DMSO-d₆) δ) 13.1 (1H), 10.45 (1H), 8.64 (1H),7.37 (4H), 7.20 (1 H), 4.75 (2H), 4.54 (2H); HPLC ret time=2.65 min; MS(ES−) m/z 347. The title compound is also a compound of formula I.

[0540] PREPARATION 14.N-(4-chlorobenzyl)-2-(hydroxymethyl)-4-{2-[methoxy(methyl)amino]-2-oxoethyl}-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0541] A mixture ofN-(4-chlorobenzyl)-2-(hydroxymethyl)-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(100 mg, 0.288 mmol), potassium carbonate (60 mg, 0.43 mmol) and2-chloro-N-methoxy-N-methylacetamide (200 mg) in DMF (1.5 mL) was shakenat room temp. for 48 hrs. The mixture was diluted with water (5 mL), andthe resulting solid was collected by filtration. The crude solid wasrecrystallized from aq. ethanol to afford title compound (90 mg). Thetitle compound is also a compound of formula I.

[0542] Physical characteristics are as follows:

[0543]¹H NMR (400 MHz, DMSO-d₆) δ) 10.45 (1H), 8.73 (1H), 7.37 (4H);7.26 (1H), 5.91 (1H), 5.47 (2H), 4.74 (2H), 4.54 (2H), 3.86 (3H), 3.16(3H); HPLC ret time=2.86 min; MS (ES+) m/z 450, 452.

[0544] PREPARATION 15.N-(4-chlorobenzyl)-2-(chloromethyl)-4-{2-[methoxy(methyl)amino]-2-oxoethyl}-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0545] To a mixture ofN-(4-chlorobenzyl)-2-(hydroxymethyl)-4-{2-[methoxy(methyl)amino]-2-oxoethyl}-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (80 mg, 0.18 mmol), collidine (59 μL, 0.44mmol) and DMAP (3.2 mg) in DMF (2.6 mL) was added methanesulfonylchloride (35 μL, 0.44 mmol). The reaction was stirred at roomtemperature for 24 hrs, then cooled to 0° C. before the addition ofwater (5 mL). The resulting ppt was collected by filtration and washedwith water and dried in vacuo, leaving the title compound as anoff-white solid (80 mg). The title compound is also a compound offormula I.

[0546] Physical characteristics are as follows:

[0547]¹H NMR (400 MHz, DMSO-d₆) δ) 10.3 (1H), 8.78 (1 H), 7.54 (1H),7.38 (4H), 5.50 (2H), 5.12 (2H), 4.55 (2H), 3.86 (3H), 3.17 (3H); HPLCret time 3.69 min.; MS (ES+) m/z 468, 470.

Example 15N-(4-chlorobenzyl)-2-{[[2-(2-furyl)-2-hydroxyethyl](methyl)amino]methyl}-4-{2-[methoxy(methyl)amino]-2-oxoethyl}-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0548]

[0549] Diisopropylethylamine (34 μL, 0.19 mmol) was added to a mixtureofN-(4-chlorobenzyl)-2-(chloromethyl)-4-{2-[methoxy(methyl)amino]-2-oxoethyl}-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(60 mg, 0.13 mmol) and 1-(2-furyl)-2-(methylamino)ethanol (27 mg, 0.19mmol) in DMF (2.0 mL). The mixture was shaken at 60° C. for 3 hrs. Thereaction was cooled to room temperature before the addition of water (5mL). The resulting ppt was collected by filtration and washed withwater. After drying in vacuo, the title compound was obtained as a paleyellow solid (41 mg).

[0550] Physical characteristics are as follows:

[0551]¹H NMR (400 MHz, DMSO-d₆) δ) 10.45 (1H), 8.71 (1H), 7.56 (1H),7.37 (4H), 7.28 (1H), 6.39 (1H), 6.29 (1H), 5.45 (2H), 5.31 (1H), 4.75(1H), 4.55 (2H), 3.85 (5H), 3.16 (3H), 2.76 (2H), 2.27 (3H); HPLC rettime=2.51 min; MS (ES+) m/z 573, 575.

Example 16N-(4-chlorobenzyl)-2-{[(2-hydroxy-2-pyrazin-2-ylethyl)(methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(enantiomer B).

[0552]

[0553] Racemic 2-(methylamino)-1-pyrazin-2-ylethanol (prepared from2-acetylpyrazine by the procedure outlined in Preparations 10 and 11)was separated into individual enantiomers via chiral HPLC (5×50 cmChiralpak AD column, 0.1% diethylamine/ethanol eluant, 70 mL/min flowrate, 310 mg sample loading). The slower eluting enantiomer (−opticalrotation, 89% ee) was used to prepare the title compound (as describedin Example 12). Recrystallization from acetonitrile/water afforded thetitle compound (38 mg) as a pale yellow solid.

[0554] Physical characteristics are as follows:

[0555]¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (1 H), 8.74 (1H), 8.65 (1H),8.54 (2H), 7.37 (5H), 5.65 (1H), 4.89 (1H), 4.54 (2H), 3.97 (3H), 3.89(2H), 2.84 (2H), 2.13 (3H); MS (ES−) 496, 498; Anal. Found: C, 56.39; H,4.81; N, 12.90.

Example 17N-(4-chlorobenzyl)-2-{[(2-hydroxy-2-pyrazin-2-ylethyl)(methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(enantiomer A).

[0556]

[0557] Racemic 2-(methylamino)-1-pyrazin-2-ylethanol (prepared from2-acetylpyrazine by the procedure outlined in Preparations 10 and 11)was separated into individual enantiomers via chiral HPLC (5×50 cmChiralpak AD column, 0.1% diethylamine/ethanol eluant, 70 mL/min flowrate, 310 mg sample loading). The faster eluting enantiomer (+opticalrotation, 95% ee) was used to prepare the title compound (as describedin Example 12). Recrystallization from acetonitrile/water afforded thetitle compound (38 mg) as a pale yellow solid.

[0558] Physical characteristics are as follows:

[0559]¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (1 H), 8.74 (1H), 8.65 (1H),8.54 (2H), 7.37 (5H), 5.65 (1H), 4.89 (1H), 4.54 (2H), 3.97 (3H), 3.89(2H), 2.84 (2H), 2.13 (3H); MS (ES−) 496, 498; Anal. Found: C, 56.63; H,4.84; N, 12.73.

Example 182-{[(1-benzyl-2-hydroxyethyl)(methyl)amino]methyl}-N-(4-chlorobenzyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0560]

[0561] A mixture ofN-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(50 mg, 0.13 mmol), racemic 2-(methylamino)-3-phenylpropan-1-ol(Tetrahedron 2001, 57, 3425)(33 mg, 0.20 mmol) and diisopropylethylamine(35 μL, 0.20 mmol) in dry DMF (2.7 mL) was heated to 60° C., becoming asolution. The reaction was stirred for 10 hours at that temperature.After cooling to room temperature, the solution was diluted with water(7 mL). The resulting milky suspension was stirred vigorously for 30minutes, and then left standing overnight in the refrigerator. Themixture was filtered, and the collected solid was washed with water anddried in vacuo, leaving a white solid. Recrystallization fromacetonitrile (5 mL, dissolved with warming and then cooled to 0° C.overnight) gave the title compound (49 mg) as a white solid.

[0562] Physical characteristics are as follows:

[0563]¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (1 H), 8.64 (1 H), 7.41, 7.17(10 H), 4.53 (3 H), 4.01 (2 H), 3.95 (3 H), 3.59 (I H), 3.46 (1 H), 2.98(1 H), 2.72 (2 H), 2.32 (3 H); Anal. Found: C, 62.97; H, 5.52; N, 8.18;MS (ESI+) for C₂₇H₂₈ClN₃O₃S m/z 510, (M+H)⁺; HRMS (FAB) calcd forC₂₇H₂₈ClN₃O₃S+H 510.1618, found 510.1611.

[0564] PREPARATION 16. N-[4-(2-bromoacetyl)phenyl]acetamide

[0565] To a suspension of 4-acetamidoacetophenone (Lancaster, 5.32 g,0.03 mol) in 1,4-dioxane/diethyl ether (100 mL, 1:2, v/v) was addedbromine (1.53 mL, 0.03 mol) via a syringe. The reaction mixture wasstirred at room temperature for 4 hours until the color of the mixturewas changed from brown to white. The solid was collected by filtration,washed with diethyl ether, and dried under high vacuum to give the titlecompound as a white solid (4.8 g).

[0566] Physical characteristics are as follows:

[0567]¹H NMR (400 MHz, DMSO-d₆) δ 10.36 (1 H), 7.96 (2 H), 7.73 (2 H),4.85 (2 H), 2.10 (3 H); MS (ESI+) for C₁₀H₁₀BrNO₂ m/z 256 (M+H)⁺, 258.

[0568] PREPARATION 17. N-[4-(2-bromo-1-hydroxyethyl)phenyl]acetamide

[0569] To a solution of N-[4-(2-bromoacetyl)phenyl]acetamide (2.1 g,0.0082 mol, in 30 mL of methanol) was introduced solid NaBH₄ (1.0 g,0.026 mol) at 0° C. and stirred at that temperature for 15 minutes. Themixture was diluted with diethyl ether (20 mL) and water (20 mL). Theether phase was separated and the aqueous phase was extracted withdiethyl ether. The ether phases were combined and washed with brine,dried. Purification on a silica gel column gave the title compound as awhite solid (0.40 g).

[0570] Physical characteristics are as follows:

[0571]¹H NMR (400 MHz, DMSO-d₆) δ 9.92 (I H), 7.52 (2 H), 7.29 (2 H),5.73 (1 H), 4.72 (1 H), 3.61 (1 H), 3.53 (1 H), 2.02 (3 H); MS (ESI+)for C₁₀H₁₂BrNO₂ m/z 258 (M+H)⁺, 260.

[0572] PREPARATION 18.N-{4-[1-hydroxy-2-(methylamino)ethyl]phenyl}acetamide

[0573] To a solution of N-[4-(2-bromo-1-hydroxyethyl)phenyl]acetamide(0.40 g, in 10 mL of methanol) was introduced methylamine (10 mL, 2.0 Min methanol) at 0° C. The reaction mixture was warmed to roomtemperature after 30 minutes, and stirred at that temperature for 2hours. The solvent and excess methylamine was evaporated. The residuewas dissolved in methanol (5 mL) and stirred with resin (BioRad 50W×2,0.5 g) overnight. The resin was collected by filtration, washed withmethanol. The product on the resin was washed off with NH₄OH/CH₃OH (10%NH₄OH aqueous solution (Aldrich, 29.4% NH₃) in methanol, v/v). Thesolution was concentrated to give the title compound as a white solid(0.16 g).

[0574] Physical characteristics are as follows:

[0575]¹H NMR (400 MHz, DMSO-d₆) δ 9.89 (1 H), 7.50 (2 H), 7.23 (2 H),5.15 (1 H), 4.56 (1 H), 2.59, 2.53 (2 H), 2.29 (3 H), 2.02 (3 H); MS(ESI+) for C₁₁H₁₆N₂O₂ m/z 209 (M+H)⁺, 191.

Example 192-{[{2-[4-(acetylamino)phenyl]-2-hydroxyethyl}(methyl)amino]methyl}-N-(4-chlorobenzyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0576]

[0577] A mixture ofN-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(50 mg, 0.13 mmol),N-{4-[1-hydroxy-2-(methylamino)ethyl]phenyl}acetamide (42 mg, 0.20 mmol)and diisopropylethylamine (40 μL, 0.23 mmol) in dry DMF (2.7 mL) washeated to 60° C., becoming a solution. The reaction was stirred for 7hours at that temperature. After cooling to room temperature, thesolution was diluted with water (7 mL). The resulting milky suspensionwas stirred vigorously for 30 minutes, and then left standing overnightin the refrigerator. The mixture was filtered, and the collected solidwas washed with water and dried in vacuo, leaving a white solid.Recrystallization from acetonitrile/water (dissolved with 3 mL ofwarming acetonitrile, cooled to room temperature, diluted with 2 mL ofwater, and then cooled to 0° C. overnight) gave the title compound (42mg) as a white solid.

[0578] Physical characteristics are as follows:

[0579]¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (1 H), 9.88 (1 H), 8.66 (1 H),7.50 (2 H), 7.38 (5 H), 7.25 (2 H), 5.09 (1 H), 4.71 (1 H), 4.54 (2 H),3.97 (3 H), 3.90 (2 H), 2.68, 2.53 (2 H), 2.30 (3 H), 2.02 (3 H); Anal.Found: C, 58.88; H, 5.33; N, 9.81. HRMS (FAB) calcd for C₂₈H₂₉ClN₄O₄S+H553.1676, found 553.1675.

Example 20N-(4-chlorobenzyl)-2-{[[(2S)-2-hydroxy-2-pyridin-3-ylethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0580]

[0581] A mixture ofN-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(167 mg, 0.44 mmol), (1S)-2-(methylamino)-1-pyridin-3-ylethanol(Preparation 29) (100 mg, 0.66 mmol) and diisopropylethylamine (115 μL,0.66 mmol) in dry DMF (8 mL) was heated to 60° C., becoming a solution.The reaction was stirred for 7 hours at that temperature. After coolingto room temperature, the solution was diluted with water (12 mL). Theresulting milky suspension was stirred vigorously for 30 minutes, andthen left standing overnight in the refrigerator. The mixture wasfiltered, and the collected solid was washed with water and dried invacuo, leaving a white solid. Recrystallization from /water (dissolvedwith warming 5 mL of acetonitrile, then cooled to 0° C. and then dilutedwith 1 mL of water, left overnight) gave the title compound (125 mg) asa white solid.

[0582] Physical characteristics are as follows:

[0583]¹H NMR (400 MHz, DMSO-d₆) δ 10.47 (1 H), 8.66 (1 H), 8.55 (1 H),8.45 (1 H), 7.74 (1 H), 7.38 (7 H), 5.39 (1 H), 4.83 (1 H), 4.54 (2 H),4.00, 3.84 (6 H), 2.75, 2.62 (2 H), 2.31 (3 H); MS (CI) forC₂₅H₂₅ClN₄O₃S m/z 497 (M+H)⁺, 499, 498, 497, 347, 153, 125, 108, 96, 69,61; HRMS (FAB) calcd for C₂₅H₂₅ClN₄O₃S+H 497.1414, found 497.1436.

Example 21N-(4-chlorobenzyl)-2-{[[(2R)-2-hydroxy-2-pyridin-2-ylethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0584]

[0585] A mixture ofN-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(113 mg, 0.30 mmol), (1R)-2-(methylamino)-1-pyridin-2-ylethanol(Preparation 28) (100 mg, 0.44 mmol) and diisopropylethylamine (230 μL,1.32 mmol) in dry DMF (8 mL) was heated to 60° C., becoming a solution.The reaction was stirred for 7 hours at that temperature. After coolingto room temperature, the solution was diluted with water (12 mL). Theresulting milky suspension was stirred vigorously for 30 minutes, andthen left standing overnight in the refrigerator. The mixture wasfiltered, and the collected solid was washed with water and dried invacuo, leaving a white solid. Recrystallization from acetonitrile/water(dissolved with warming 5 mL of acetonitrile, then cooled to 0° C. andthen diluted with 1 mL of water, left overnight) gave the title compound(98 mg) as a white solid.

[0586] Physical characteristics are as follows:

[0587]¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (1 H), 8.66 (1 H), 8.48 (1 H),7.78 (1 H), 7.50 (1 H), 7.41, 7.33 (6 H), 7.25 (1 H), 5.38 (1 H), 4.83(1 H), 4.54 (2 H), 3.98 (4 H), 3.92 (2 H), 2.82 (1 H), 2.71 (1 H), 2.33(3 H); Anal. Found: C, 59.78; H, 5.19; N, 10.38; MS (CI) forC₂₅H₂₅ClN₄O₃S m/z 497 (M+H)⁺, 499, 497, 347, 153, 122, 108, 106, 96, 69,61; HRMS (FAB) calcd for C₂₅H₂₅ClN₄O₃S+H 497.1414, found 497.1412.

Example 22N-(4-chlorobenzyl)-2-{[(2-hydroxy-2-pyrimidin-2-ylethyl)(methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0588]

[0589] A mixture ofN-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(100 mg, 0.26 mmol), 2-(methylamino)-1-pyrimidin-2-ylethanol(Preparation 23)(59 mg, 0.39 mmol) and diisopropylethylamine (67 μL,0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution.The reaction was stirred for 7 hours at that temperature. After coolingto room temperature, the solution was diluted with water (10 mL). Theresulting milky suspension was stirred vigorously for 30 minutes, andthen left standing overnight in the refrigerator. The mixture wasfiltered, and the collected solid was washed with water and dried invacuo, leaving a white solid. Recrystallization from acetonitrile/water(dissolved with warming 5 mL of acetonitrile, then cooled to 0° C. andthen diluted with 2 mL of water, left overnight) gave the title compound(60 mg) as a white solid.

[0590] Physical characteristics are as follows:

[0591]¹H NMR (400 MHz, DMSO-d₆) δ 10.47 (1 H), 8.78 (2 H), 8.65 (1 H),7.43, 7.33 (6 H), 5.36 (1 H), 4.86 (1 H), 4.53 (2 H), 3.97 (3 H), 3.87(2 H), 2.98 (1 H), 2.82 (1 H), 2.29 (3 H); MS (CI) for C₂₄H₂₄C1N₅O₃S m/z498 (M+H)⁺, 500, 498, 349, 347, 154, 126, 109, 107, 96, 61; HRMS (FAB)calcd for C₂₄H₂₄ClN₅O₃S+H 498.1366, found 498.1385.

Example 23N-(4-chlorobenzyl)-2-{[[2-hydroxy-2-(1H-indol-3-yl)ethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0592] A mixture ofN-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(100 mg, 0.26 mmol), 1-(1H-indol-3-yl)-2-(methylamino)ethanol(Khim.-Farm. Zh. 1970, 4, 5-9)(75 mg, 0.39 mmol) anddiisopropylethylamine (180 μL, 1.04 mmol) in dry DMF (5 mL) was heatedto 60° C., becoming a solution. The reaction was stirred for 5 hours atthat temperature. After cooling to room temperature, the solution wasdiluted with water (15 mL). The resulting milky suspension was stirredvigorously for 30 minutes, and then left standing overnight in therefrigerator. The mixture was filtered, and the collected solid waswashed with water and dried in vacuo, leaving a white solid.Recrystallization from acetonitrile/water (dissolved with warming 5 mLof acetonitrile, then cooled to 0° C. and then diluted with 3 mL ofwater, left overnight) gave the title compound (59 mg) as a white solid.

[0593] Physical characteristics are as follows:

[0594]¹H NMR (400 MHz, DMSO-d₆) δ 10.87 (1 H), 10.48 (1 H), 8.66 (1 H),7.54 (1 H), 7.41, 7.31 (6 H), 7.23 (1 H), 7.03 (1 H), 6.89 (1 H), 5.07(1 H), 4.86 (1 H), 4.54 (2 H), 4.00, 3.89 (5 H), 2.83 (2 H), 2.38 (3 H);MS (CI) C₂₈H₂₇ClN₄O₃S m/z 535 (M+H)⁺, 535, 517, 347, 175, 173, 163, 146,144, 118, 61; HRMS (FAB) calcd for C₂₈H₂₇ClN₄O₃S+H 535.1570, found535.1581.

Example 242-{[[2-(3-aminophenyl)-2-hydroxyethyl](methyl)amino]methyl}-N-(4-chlorobenzyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide

[0595]

[0596] A mixture ofN-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(80 mg, 0.21 mmol), 1-(3-aminophenyl)-2-(methylamino)ethanol (Zhur.Obshchei Khim. (J. Gen. Chem.) 1952, 22, 496-502)(53 mg, 0.32 mmol) anddiisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to60° C., becoming a solution. The reaction was stirred for 5 hours atthat temperature. After cooling to room temperature, the solution wasdiluted with water (15 mL). The resulting milky suspension was stirredvigorously for 30 minutes, and then left standing overnight in therefrigerator. The mixture was filtered, and the collected solid waswashed with water and dried in vacuo, leaving a white solid.Recrystallization from acetonitrile/water (dissolved with warming 5 mLof acetonitrile, then cooled to 0° C. and then diluted with 3 mL ofwater, left overnight) gave the title compound (62 mg) as a white solid.

[0597] Physical characteristics are as follows:

[0598]¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (1 H), 8.66 (1 H), 7.41, 7.33 (5H), 6.92 (1 H), 6.56 (1 H), 6.46 (1 H), 6.41 (1 H), 4.96 (2 H), 4.61 (1H), 4.54 (2 H), 3.98 (3 H), 3.91 (1 H), 2.59 (1 H), 2.33 (3 H); MS (CI )for C₂₆H₂₇ClN₄O₃S m/z 511 (M+H)⁺, 513, 511, 347, 167, 165, 153, 149,139, 136, 61; HRMS (FAB) calcd for C₂₆H₂₇ClN₄O₃S+H 511.1570, found511.1562.

Example 252-{[[2-(1,3-Benzodioxol-5-yl)-2-hydroxyethyl](methyl)amino]methyl}-N-(4-chlorobenzyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0599]

[0600] A mixture ofN-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(80 mg, 0.21 mmol), 1-(1,3-benzodioxol-5-yl)-2-(methylamino)ethanol(Journal of Organometallic Chemistry, 1998, 339, 267-75) (62 mg, 0.32mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) washeated to 60° C., becoming a solution. The reaction was stirred for 5hours at that temperature. After cooling to room temperature, thesolution was diluted with water (15 mL). The resulting milky suspensionwas stirred vigorously for 30 minutes, and then left standing overnightin the refrigerator. The mixture was filtered, and the collected solidwas washed with water and dried in vacuo, leaving a white solid.Recrystallization from acetonitrile/water (dissolved with warming 3 mLof acetonitrile, then cooled to 0° C. and then diluted with 2 mL ofwater, left overnight) gave the title compound (74 mg) as a white solid.

[0601] Physical characteristics are as follows:

[0602]¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (1 H), 8.66 (1 H), 7.41, 7.33 (5H), 6.88 (1 H), 6.82 (2 H), 5.97 (2 H), 5.11 (1 H), 4.68 (1 H), 4.54 (2H), 3.98 (3 H), 3.89 (2 H), 2.68, 2.54 (2 H), 2.30 (3 H); Anal. Found:C, 59.82; H, 4.90; N, 7.71; MS (CI) for C₂₇H₂₆ClN₃O₅S m/z 540 (M+H)⁺,540, 347, 196, 194, 182, 180, 178, 168, 165, 61; HRMS (FAB) calcd forC₂₇H₂₆ClN₃O₅S+H 540.1360, found 540.1355.

Example 26N-(4-chlorobenzyl)-2-{[[2-hydroxy-2-(4-methoxyphenyl)ethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide.

[0603]

[0604] A mixture ofN-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide(80 mg, 0.21 mmol), 1-(4-methoxyphenyl)-2-(methylamino)ethanol(Tetrahedron 1999, 55, 4831-4842) (58 mg, 0.32 mmol) anddiisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to60° C., becoming a solution. The reaction was stirred for 7 hours atthat temperature. After cooling to room temperature, the solution wasdiluted with water (15 mL). The resulting milky suspension was stirredvigorously for 30 minutes, and then left standing overnight in therefrigerator. The mixture was filtered, and the collected solid waswashed with water and dried in vacuo, leaving a white solid.Recrystallization from acetonitrile (5 mL, dissolved with warming andthen cooled to 0° C. overnight) gave the title compound (54 mg) as awhite solid.

[0605] Physical characteristics are as follows:

[0606]¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (1 H), 8.67 (1 H), 7.38 (5 H),7.25 (2 H), 6.87 (2 H), 5.06 (1 H), 4.72 (1 H), 4.54 (2 H), 3.98 (3 H),3.90 (2 H), 3.73 (3 H), 2.67, 2.55 (2 H), 2.31 (3 H); Anal. Found: C,61.41; H, 5.42; N, 7.86; MS (CI) for C₂₇H₂₈ClN₃O₄S m/z 526 (M+H)⁺, 528,526, 349, 347, 182, 164, 154, 151, 137, 61; HRMS (FAB) calcd forC₂₇H₂₈ClN₃O₄S+H 526.1567, found 526.1580.

[0607] PREPARATION 19. 2-{1-[(Triisopropylsilyl)oxy]vinyl}pyrimidine.

[0608] 2-Acetylpyrimidine (Khim. Geterotsikl. Soedin., (7), 958-62;1981)(7.37g, 60.4mmol) and DIEA (23.4 g, 181.2 mmol) were dissolved indry CH₂Cl₂ under N₂ then cooled in an ice bath. TIPS-triflate (17.9 ml,20.4 g, 66.4 mmol) was added over 2-3 min and stirred over night. Thesolvent was evaporated and the residue treated with ether (200 ml),filtered and washed with sat. sodium bicarbonate solution (2×50 ml).Evaporation gave a quantitative yield of the silyl ether as a red oil.

[0609] Physical characteristics are as follows:

[0610] HRMS (FAB) calcd for C₁₅H₂₆N₂OSi+H 279.1892, found 279.1898. ¹HNMR (300 MHz, CDCl₃) δ 1.15 (18 H), 1.31 (3 H), 4.90 (1 H), 5.82 (1 H),7.16 (1 H), 8.74 (2 H).

[0611] PREPARATION 20.2-{2-Chloro-1-[(triisopropylsilyl)oxy]ethenyl}pyrimidine. 737980

[0612] N-chlorosuccinimide (9.97 g, 74.7 mmol) was added to a solutionof 2-{1-[(Triisopropylsilyl)oxy]vinyl}pyrimidine (17.3 g, 62.2 mmol) indry THF (120 ml) under N₂ then heated at 65° for 5 hr. After cooling,ether (275 ml) was added and then washed with sat. sodium bicarbonatesolution (2×100 ml). The organic layer was dried over sodium sulfate,filtered and evaporated to leave an amber oil. This oil was dissolved inhexane (250 ml), treated with MgSO₄ and filtered. Evaporation affordedthe product as a yellow oil in quantitative yield.

[0613] Physical characteristics are as follows:

[0614] HRMS (FAB) calcd for C₁₅H₂₅ClN₂OSi+H 313.1503, found 313.1509. ¹HNMR (300 MHz, CDCl₃) δ 1.13 (18 H), 1.33 (3 H), 6.97 (1 H), 7.17 (1 H),8.68 (2 H).

[0615] PREPARATION 21. 2-Chloro-1-pyrimidin-2-ylethanone.

[0616] 2-{2-Chloro-1-[(triisopropylsilyl)oxy]ethenyl}pyrimidine (19.4 g,62.2 mmol) was dissolved in acetonitrile (90 ml) and treated with 48% HF(10 ml) for 4 hr. Sat. sodium bicarbonate solution (ca. 250 ml) was thenadded carefully to pH7 and the mixture extracted with CH₂Cl₂ (3×200 ml).After drying (Na₂SO₄), filtration and evaporation two oils wereobtained, the upper colorless oil was decanted off and discarded and thelower oil crystallized to an oily solid. Chromatography over silica gel(500 g) eluting with 2.5% MeOH—CHCl₃ gave the product as a pale yellowsolid (6.50 g) mp:73-80°.

[0617] Physical characteristics are as follows:

[0618] Anal. Found: C, 46.05; H, 3.09; N, 17.93.

[0619] PREPARATION 22. rac-2-Chloro-1-pyrimidin-2-ylethanol.

[0620] 2-Chloro-1-pyrimidin-2-ylethanone (6.15 g, 39.3 mmol) wasdissolved in ethanol (125 ml) and CeCl₃.7H₂O (14.64 g, 39.3 mmol) wasadded. Stirring was continued for 10 min then sodium borohydride (1.49g, 39.3 mmol) was added over 2 min. After 1 hr the solid was filteredand the filtrate evaporated. Sat. ammonium chloride solution (25 ml) wasadded followed by brine (250 ml) and the mixture adjusted to pH3-4 with1N.HCl. Extraction with ethyl acetate (3×250 ml) afforded an amber oilwhich was chromatographed over silica gel (150 g) to give the product asa pale yellow oil (3.85 g)

[0621] Physical characteristics are as follows:

[0622] Anal. Found: C, 45.08; H, 4.47; N, 17.46.

[0623] PREPARATION 23. rac-2-(Methylamino)-1-pyrimidin-2-ylethanol.

[0624] In a pressure bottle was placed 2-chloro-1-pyrimidin-2-ylethanol(3.525 g, 22.24 mmol), sodium iodide (0.344 g, 2.29 mmol) and a2M.methylamine solution (160 ml, 320 mmol) in methanol. The bottle wassealed and heated at 62° for 17 hr. The solvent was evaporated and theresidue stirred with 10% MeOH—CHCl₃. Filtration and evaporation gave adark oil that was chromatographed over silica gel (90 g) eluting with5-10% MeOH—CH₂Cl₂ containing 1% triethylamine The product was obtainedas an amber oil (1.625 g).

[0625] Physical characteristics are as follows:

[0626]¹H NMR (400 MHz, CDCl₃) δ 2.53 (3 H), 3.03 (1 H), 3.21 (1 H), 3.66(2 H), 5.03 (1 H), 7.26 (1 H), 8.77 (2H); HRMS (ESI) calcd forC₇H₁₁N₃O+H 154.0980, found 154.0979.

[0627] PREPARATION 24. 2-{1-[(triisopropylsilyl)oxy]vinyl}pyridine.

[0628] 2-Acetylpyridine (50 g, 0.413 mol) is placed in a 2 L 1N roundbottom flask and anhydrous CH₂Cl₂ (Alrdich Sure Seal®, 0.65 L) is added,followed by the addition of i-Pr₂NEt (160.27 g, 1.24 mol, 3 eq., 216mL). The flask is equipped with a 125 mL pressure equalized droppingfunnel, and the mixture is placed under nitrogen and cooled in anice-water bath. To the chilled ketone/amine mixture is added TIPSOTf(139.7 g, 0.456 mol, 1.1 eq., 122.6 mL) over 1.5 hours. The mixture isallowed to warm to room temperature overnight. The reaction mixture isconcentrated in vacuo on a rotary evaporator (T≦25° C.) to give a yellowoil and a white solid. The flask contents are transferred to a 2 Lseparatory funnel with ether (1.2 L) resulting in the formation ofadditional white solid material (likely iPr₂(Et)NH+⁻OTf which might beremoved by filtration but is not in this experiment) and the mixture iswashed with saturated aq. NaHCO₃ (2×0.65 L). The organic phase isseparated, dried over Na₂SO₄, then is concentrated in vacuo to furnishthe crude 2-[1-Tri-isopropylsilyloxy-vinyl]-pyridine (131.5 g) as ayellow-orange oil. This crude material is not further purified, but isimmediately carried to the next step.

[0629] Physical characteristics are as follows:

[0630]¹H—NMR (400 MHz, CDCl₃): δ=8.57, 7.71, 7.21, 5.65, 4.58, 1.36,1.15.

[0631] PREPARATION 25.2-{2-chloro-1-[(triisopropylsilyl)oxy]ethenyl}pyridine

[0632] Crude 2-{1-[(triisopropylsilyl)oxy]vinyl}pyridine (131.5 g,assumed 0.413 mmol) is placed in a 2 L, 1N round bottom flask anddissolved in anhydrous THF (Aldrich Sure Seal, 0.6 L). The flask isequipped with a reflux condenser and the apparatus is placed undernitrogen. NCS (60.66 g, 0.454 mol, 1.1 eq.) is added and the mixture isheated to reflux and maintained at reflux for 2 hours. The reactionmixture is cooled to room temperature, poured into a 4 L separatoryfunnel containing ether (1.5 L), and is washed with saturated aq. NaHCO₃(2×0.7 L). The organic phase is separated, dried (Na₂SO₄), andconcentrated in vacuo affords the target (117.5 g) as a yellow-orangeoil. The crude material is not further purified, but is immediatelycarried into the next step.

[0633] Physical characteristics are as follows:

[0634]¹H-NMR (400 MHz, CDCl₃):δ=8.53, 7.71, 7.52, 7.22, 6.58, 1.21,1.13.

[0635] PREPARATION 26. 2-chloro-1-pyridin-2-ylethanone

[0636] Crude 2-{2-chloro-1-[(triisopropylsilyl)oxy]ethenyl}pyridine(117.3 g, 0.376 mol) is placed in a 4 L plastic bottle and is dissolvedin acetonitrile (0.4 L). To the stirring solution is added 48% aqueousHF (170 mL, 0.45 mL/mmol) and the progress of the reaction is monitoredby reverse phase analytical HPLC. After. Ca. 2 hours the reaction isjudged to be complete, and the pH of the solution is carefully adjustedto ca. 8 with saturated aq. NaHCO₃. The mixture is poured into aseparatory funnel containing CH₂Cl₂ (1.5 L). The organic phase isremoved and the aq. layer is extracted with CH₂Cl₂ (2×1.0 L). Thecombined organic layers are dried (Na₂SO₄), and concentration in vacuoaffords the title compound (49.5 g) as a tan solid (after cooling). Thecrude material is judged to be quite pure by ¹H—NMR and HPLC and is usedas is in the Noyori asymmetric reduction.

[0637] Physical characteristics are as follows:

[0638]¹H—NMR (400 MHz, CDCl₃): δ=8.66, 8.09, 7.88, 7.54, 5.12.

[0639] PREPARATION 27. (1S)-2-chloro-1-pyridin-2-ylethanol

[0640] [RuCl₂(η⁶-p-cymene)]₂ (0.84 g, 1.37 mmol), Et₃N (0.67 g, 6.66mmol, 0.93 mL), and (1R,2R)-N-p-toluenesulfonyl-1,2-diphenylethylenediamine (1.0 g, 2.72 mmol,1.78 mol % based upon ketone) are combined in a 500 mL 1N round bottomflask. i-PrOH is added, a reflux condenser is attached and the mixtureis warmed under reflux, and maintained, for 1 hour. Cool to roomtemperature and concentrate in vacuo (rotovapor followed by vacuum pump)to furnish the catalyst as a brown powdery solid. To the catalyst isadded anhydrous DMF (Aldrich Sure Seal, 225 mL), followed in order by2-chloro-1-pyridin-2-ylethanone (23.88 g, 0.153 mol) and HCOOH/Et₃N(5:2, Fluka, 55 mL). After ca. 2-3 minutes of stirring (roomtemperature) bubbles (presumed to be CO₂) are apparent, emanating fromthe stirring vortex of the red-black solution. Reaction progress ismonitored by reverse phase analytical HPLC, and after 65 minutes ofstirring, the starting material is consumed (95:5 NaH₂PO₄/H₃PO₄ bufferedwater/CH₃CN to 5:95, 17 minutes; retention time of startingchloroketone: 7.39 minutes, retention time of halohydrin 2.66 minutes).Quench the reaction by adding MeOH (25 mL), stir 5 minutes and then theDMF, etc is removed in vacuo (cold finger rotovapor, vacuum pump) togive a red-black viscous oil. The crude material is taken up inEt₂O/CH₂Cl₂ (4:1, 1.25 L), placed in a 3 L separatory funnel, washedwith saturated aq. NaHCO₃ (1.0 L), brine (1.0 L), and dried (Na₂SO₄).Filtration and concentration in vacuo affords the crude product as ared-orange oil which is purified by chromatography on a column of silicagel (70 mm OD, 250 g 230-400 mesh, packed hexanes; compound applied inCH₂Cl₂/hexanes 60:40; eluted with hexanes/Et₂O (75:25 2 L; 65:35 2 L;55:45 2 L; 350 mL fractions) using the flash technique. Fractions 11-17are combined to afford 16.41 g of the target as a pale yellow solid.

[0641] Physical characteristics are as follows:

[0642] MP: 49-50° C.; ¹H—NMR (400 MHz, CDCl₃): δ=8.60, 7.77, 7.58, 7.30,5.00, 4.20, 3.85; EI-MS (70EV): 160(M⁺, 35), 158(M⁺, 90), 122(90),106(base); Anal. Found: C, 53.27; H, 5.19; N, 8.81, Cl, 22.29; SpecificRotation [α]^(D) ₂₅=62 (c 0.94, methanol).

[0643] PREPARATION 28. (1R)-2-(methylamino)-1-pyridin-2-ylethanol

[0644] (1S)-2-chloro-1-pyridin-2-ylethanol (6.0 g, 38 mmol) and NaI(0.57 g, 3.8 mmol) are combined in a 500 mL, plastic coated, thickwalled bottle and are covered with 2M MeNH₂ in MeOH (0.19 L). The Teflonstopper is wrapped in Teflon tape, the bottle is sealed. Stirring isstarted, and the bottle is immersed in a 60° C. oil bath for 16 hours.The yellow-brown mixture is cooled to room temperature and analyzed byanalytical reverse phase HPLC, which indicated that the reaction iscomplete (retention time starting material=2.44 minutes; retention timeproduct=1.24 minutes). Concentration in vacuo affords the crude productas a yellow oil, which is treated with CH₂Cl₂-THF (0.25 L, 10:90) togive a yellow solution and a white precipitate. The precipitate isremoved by filtration, is rinsed with CH₂Cl₂-THF (10:90) and thecombined filtrated are concentrated in vacuo to give a yellow-brown oil.The crude product is purified by chromatography on a column of silicagel (70 mm OD, 250 g, 230-400 mesh; packed with CH₂Cl₂-MeOH 90:10;eluted with CH₂Cl₂-MeOH 90:10, 2 L, 500 mL fractions; CH₂Cl₂-MeOH—NH₄OH89:10:1, 8 L, 350 mL fractions) using the flash technique. Fractions14-30 are combined to provide 3.18 g of the target as an amber oil.

[0645] Physcial characteristics are as follows:

[0646]¹H—NMR (400 MHz, DMSO-d₆): δ=8.49, 7.79, 7.52, 7.25, 4.75, 2.90,2.67, 2.32; EI-MS (70EV): 153(M⁺, base), 135(18), 122(20), 108(62); HRMS(FAB): Found 153.1009; Specific Rotation [α]^(D) ₂₅=49 (c 0.36, CH₂Cl₂).

[0647] PREPARATION 29. (1S)-2-(methylamino)-1-pyridin-3-ylethanol

[0648] As described for the preparation of(1R)-2-(methylamino)-1-pyridin-2-ylethanol (Preparations 27-28),3-chloroacetylpyridine (Chem. Ber. 1951, 84, 147-149) is converted tothe title compound, isolated as a pale yellow amorphous solid.

[0649] Physical characteristics are as follows:

[0650] OAMS supporting ions at: ESI+153.1 ESI-151.1; HRMS (ESI) Found153.1017; Specific Rotation [α]²⁵ _(D)=70° (c 1.03, methylene chloride);Anal. Found: C, 62.39; H, 7.93; N, 18.00.

[0651] All cited publications, patents, and patent documents areincorporated by reference herein, as though individually incorporated byreference. The invention has been described with reference to variousspecific and preferred embodiments and techniques. However, it should beunderstood that many variations and modifications may be made whileremaining within the spirit and scope of the invention.

What is claimed is:
 1. A compound of formula I:

wherein: G is phenyl substituted with from one to five R¹ substituents;each R¹ is independently (a) Cl, (b) Br, (c) F, (d) cyano, (e)C₁₋₇alkyl, or (f) NO₂; R² is (a) H, (b) R⁵, (c) NR⁷R⁸, (d) SO₂R⁹, or (e)OR⁹; R³ is (a) H, (b) halo, (c) aryl, (d) S(O)_(m)R⁶, (e) (C═O)R⁶, (f)(C═O)OH, (g) (C═O)OR⁹, (h) cyano, (i) het, wherein the het is bound viaa carbon atom, (j) OR¹⁴, (k) NR⁷R⁸, (l) SR¹⁴, (m) NHSO₂R¹², (n)C₁₋₇alkyl which is optionally partially unsaturated and optionallysubstituted by one or more R¹¹¹ substituents, or (o) C₃₋₈cycloalkylwhich is optionally partially unsaturated and optionally substituted byone or more R¹¹, or substituted by one or more C₁₋₇alkyl which C₁₋₇alkylis optionally substituted by one or more R¹¹; R⁵ is (a)(CH₂CH₂O)_(i)R¹⁰, (b) het, wherein the het is bound via a carbon atom,(c) aryl, (d) C₁₋₇alkyl which is optionally partially unsaturated andoptionally substituted by one or more R¹¹ substituents, or (e)C₃₋₈cycloalkyl which is optionally partially unsaturated and optionallysubstituted by one or more R¹¹, or substituted by one or more C₁₋₇alkylwhich C₁₋₇alkyl is optionally substituted by one or more R¹¹; R⁶ is (a)C₁₋₇alkyl optionally substituted by aryl, het, OR¹³, SR¹³, NR¹³R¹³,halo, or C₃₋₈cycloalkyl, which C₃₋₈cycloalkyl is optionally substitutedwith OR¹³, (b) C₃₋₈cycloalkyl which is optionally partially unsaturatedand optionally substituted by one or more halo, OR¹³, SR¹³, or NR¹³R¹³substituents, (c) NR⁷R⁸, (d) aryl, or (e) het, wherein the bet is boundvia a carbon atom; R⁷ and R⁸ are independently a. H, b. aryl, c.C₁₋₇alkyl which is optionally partially unsaturated and optionallysubstituted by one or more NR¹³R¹³, OR¹⁴, SR¹⁴, S(O)_(m)R⁹,P(═O)(OR¹⁴)(R¹⁴), CONR¹⁴R¹⁴, CO₂R¹³, (C═O)R⁹, het, aryl, cyano, or halosubstituents, d. C₃₋₈cycloalkyl which is optionally partiallyunsaturated and optionally substituted by one or more halo, OR¹³, SR¹³,oxo, or NR¹³R¹³ substituents, e. (C═O)R⁹, or f. R⁷ and R⁸ together withthe nitrogen to which they are attached form a het; R⁹ is (a) aryl, (b)het (c) C₃₋₈cycloalkyl, or (d) C₁₋₇alkyl which is optionally partiallyunsaturated and optionally substituted by one or more NR¹³R¹³, OR¹⁴,SR¹⁴, halo, CONR¹³R¹³, CO₂R¹³, het, or aryl substituents; R¹⁰ is (a) H,or (b) C₁₋₇alkyl optionally substituted by OH; R¹¹ is (a) OR¹⁴, (b)SR¹⁴. (c) NR⁷R⁸, (d) halo, (e) CONH₂, (f) CONHR⁹, (g) CONR⁹R⁹, (h) CO₂H,(i) CO₂R⁹, (j) het, (k) aryl, (l) cyano, (m) oxo, (n) SO_(m)R⁶, or (o)P(═O)(OR¹⁴)(R¹⁴); R¹² is (a) H, (b) het, (c) aryl, (d) C₃₋₈cycloalkyloptionally substituted with R¹¹, or (e) C₁₋₇alkyl optionally substitutedwith R¹¹; R¹³ is (a) H, or (b) C₁₋₇alkyl; R¹⁴ is (a) H, (b) aryl, (c)het, (d) C₁₋₇alkyl which is optionally partially unsaturated andoptionally substituted by aryl, het, OR¹³, SR¹³, NR¹³R¹³, halo, orC₃₋₈cycloalkyl which C₃₋₈cycloalkyl is optionally substituted by one ormore OR¹³, or (e) C₃₋₈cycloalkyl which is optionally partiallyunsaturated and optionally substituted by one or more halo, OR¹³, SR¹³,or NR¹³R¹³ substituents; R¹⁵ is (a) H, (b) halo, (c) OR¹³, (d) SR¹³, (e)NR¹³R¹³, (f) O(CH₂CH₂O)_(n)R¹⁰, (g) phenyl, (h) cyano, (i) nitro, (j)CONR¹³R¹³, (k) CO₂R¹³, (l) S(O)_(m)NR¹³R¹³, (m) CONHR¹³, (n)S(O)_(m)R¹⁰, (o) NR¹³COR¹³, (p) C₁₋₇alkyl which is optionally partiallyunsaturated and optionally substituted with one or more oxo, phenyl,4-morpholine, OR¹³, SR¹³, NR¹³R¹³, halo, CO₂R¹³, CONR¹³R¹³, orC₃₋₈cycloalkyl which C₃₋₈cycloalkyl is optionally substituted by one ormore OR¹³, or (q) C₃₋₈cycloalkyl which is optionally partiallyunsaturated and optionally substituted by one or more oxo, halo, OR¹³,SR¹³, C₁₋₇alkyl, CONH₂ or NR¹³R¹³ substituents; or (r) pyrimidinyl,pyridyl, pyrrolyl, pyrazinyl, pyridazinyl, imidazolyl, or pyrazolyl;each i is independently 2, 3, or 4; each n is independently 1, 2, 3, 4or 5; each m is independently 1 or 2; wherein any aryl other than G isoptionally substituted with one or more R¹⁵ substituents; and whereinany het is optionally substituted with one or more ═O, ═N—OR¹³, or R¹⁵substituents; or a pharmaceutically acceptable salt thereof.
 2. Thecompound of claim 1 wherein R¹ is F, Cl, or cyano.
 3. The compound ofclaim 2 wherein R¹ is Cl.
 4. The compound of claim 3 wherein R¹ is 4-Cl.5. The compound of claim 1 wherein R¹ is C₁₋₇alkyl.
 6. The compound ofclaim 5 wherein R¹ is methyl.
 7. The compound of claim 1 wherein R2 isH.
 8. The compound of claim 1 wherein R² is C₁₋₇alkyl which isoptionally partially unsaturated and is optionally substituted with oneor more R¹¹ substituents.
 9. The compound of claim 8 wherein R² ismethyl.
 10. The compound of claim 8 wherein R² is ethyl.
 11. Thecompound of claim 1 wherein R³ is H, halo, aryl, S(O)_(m)R⁶ (C═O)R⁶,(C═O)OH, (C═O)OR⁹, cyano, OR¹⁴, NR⁷R⁸SR¹⁴, or NHSO₂R¹².
 12. The compoundof claim 1 wherein R³ is C₁₋₇alkyl which is optionally partiallyunsaturated and optionally substituted by one or more R¹¹ substituents,or C₃₋₈cycloalkyl which is optionally partially unsaturated andoptionally substituted by one or more R¹¹ or C₁₋₇alkyl substituents. 13.The compound of claim 12 wherein R³ is hydroxymethyl.
 14. The compoundof claim 12 wherein R³ is C₂₋₇alkyl which comprises one double bond andis optionally substituted by one or more R¹¹ substituents.
 15. Thecompound of claim 12 wherein R³ is C₂₋₇alkyl which comprises one triplebond and is optionally substituted by one or more R¹¹ substituents. 16.The compound of claim 15 wherein R³ is 3-hydroxypropyn-1-yl.
 17. Thecompound of claim 1 wherein R³ is het, wherein the het is bound to thethieno ring via a carbon atom.
 18. The compound of claim 1 wherein R³ ishet, wherein the het is bound to the thieno ring via a nitrogen atom.19. The compound of claim 1 wherein R³ is H.
 20. The compound of claim 1wherein R³ is CH₂NR⁷R⁸.
 21. The compound of claim 1 wherein R³ isCH₂NR⁷R⁸ where R⁷ is C₁₋₇alkyl, and R⁸ is C₁₋₇alkyl which is optionallypartially unsaturated and is optionally substituted by one or moreNR¹³R¹³, OR¹⁴, SR¹⁴, S(O)_(m)R⁹, CONR¹³R¹³, CO₂R¹³, (C═O)R⁹, het, aryl,cyano, or halo substituents.
 22. The compound of claim 1 wherein R³ isCH₂NR⁷R⁸ where R⁷ is methyl, and R⁸ is ethyl substituted with aryl, het,or OR¹⁴.
 23. The compound of claim 1 wherein R³ is morpholinomethyl. 24.The compound of claim 1 wherein R³ isN-methyl-N-{2-(4-hydroxyphenyl)-2-hydroxyethyl}aminomethyl;N-methyl-N-{2-(3-hydroxyphenyl)-2-hydroxyethyl}aminomethyl;N-methyl-N-{2-(3-methoxyphenyl)-2-hydroxyethyl}aminomethyl;N-methyl-N-(2-furan-2-yl-2-hydroxyethyl) aminomethyl;N-methyl-N-{2-phenyl-2-hydroxyethyl}aminomethyl;N-methyl-N-{2-(1,3-thiazol-2-yl)ethyl}aminomethyl;N-methyl-N-{2-(4-methylsulfonylphenyl)-2-hydroxyethyl}aminomethyl;N-methyl-N-{2-(pyridin-2-yl)-2-hydroxyethyl}aminomethyl;N-methyl-N-(2-pyrazin-2-yl-2-hydroxyethyl) aminomethyl;N-methyl-N-[2-(5-cyanothien-2-yl)-2-hydroxyethyl]aminomethyl;N-methyl-N-(2-pyridin-2-yl-2-hydroxyethyl) aminomethyl;N-methyl-N-(2-pyrimidin-2-yl-2-hydroxyethyl) aminomethyl;N-methyl-N-[2-(4-acetylaminophenyl)-2-hydroxyethyl]aminomethyl;(R)-N-methyl-N-(2-pyridin-3-yl-2-hydroxyethyl) aminomethyl; or3-hydroxy-1-propynyl; hydroxymethyl; morpholinomethyl;(R)-N-methyl-N-{2-(pyridin-2-yl)-2-hydroxyethyl}aminomethyl;N-methyl-N-{2-indol-3-yl -2-hydroxyethyl}aminomethyl;N-methyl-N-{2-(3-aminophenyl)-2-hydroxyethyl}aminomethyl;N-methyl-N-{2-(3,4-methylenedioxyphenyl)-2-hydroxyethyl}aminomethyl; orN-methyl-N-{2-(4-methoxyphenyl)-2-hydroxyethyl}aminomethyl.
 25. Thecompound of claim 1 which is a compound of formula IV:

wherein: R¹⁶ is (a) H, (b) aryl, (c) C₁₋₇alkyl which is optionallypartially unsaturated and is optionally substituted by one or moreNR¹³R¹³, OR¹³, or SR¹³, S(O)_(m)R⁹, CONR¹⁴R¹⁴, CO₂R¹³, (C═O)R⁹, het,aryl, cyano, or halo substituents, (d) C₃₋₈cycloalkyl which isoptionally partially unsaturated and is optionally substituted by one ormore halo, OR¹³, SR¹³, oxo, or NR¹³R¹³substituents, or (e) (C═O)R⁹; andR¹⁷ is (a) aryl, or (b) het; or a pharmaceutically acceptable saltthereof.
 26. The compound of claim 25 which is a compound of formula V:

or a pharmaceutically acceptable salt thereof.
 27. The compound of claim25 which is a compound of formula VI:

or a pharmaceutically acceptable salt thereof.
 28. The compound of claim1, 25, 26, or 27 wherein G is phenyl substituted with one, two, or threeR¹ groups.
 29. The compound of claim 1, 25, 26, or 27 wherein G is4-chlorophenyl, 4-fluorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl,2,4-dichlorophenyl, 2,4-difluorophenyl, 4-chloro-2-fluorophenyl,2-chloro-4-fluorophenyl, 3,4,5-trifluorophenyl, 4-bromophenyl,4-methylphenyl, 4-cyanophenyl, or 4-nitrophenyl.
 30. The compound ofclaim 1, 25, 26, or 27 wherein G is phenyl substituted with one or twoR¹, and R² and R³ are C₁₋₇alkyl which are optionally partiallyunsaturated and optionally substituted with one or more R¹¹substituents.
 31. The compound of claim 1, 25, 26, or 27 wherein G isphenyl substituted with one R¹ at the 4-position; R² is CH₃; and R³ isC₁₋₇alkyl optionally substituted by NR⁷R⁸.
 32. The compound of claim 1,25, 26, or 27 wherein G is 4-chlorophenyl; R³ is CH₂N(CH₃)CH₂CH(OH)arylor CH₂N(CH₃)CH₂CH(OH)het; and R² is CH₃.
 33. The compound of claim 1wherein R¹⁵ is NH—C(═O)—R¹³.
 34. The compound: a)N-(4-Chlorobenzyl)-7-hydroxythieno[3,2-b]pyridine-6-carboxamide; b)N-(4-Chlorobenzyl)-4-ethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;c)N-(4-chlorobenzyl)-2-(3-hydroxyprop-1-ynyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;d)N-(4-chlorobenzyl)-4-methyl-2-(morpholin-4-ylmethyl)-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide; e)N-(4-chlorobenzyl)-2-{[[2-hydroxy-2-(3-methoxyphenyl)ethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;f)N-(4-chlorobenzyl)-2-{[[2-(2-furyl)-2-hydroxyethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide; g)N-(4-chlorobenzyl)-2-{[(2-hydroxy-2-phenylethyl)(methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;h)N-(4-chlorobenzyl)-2-{[[2-hydroxy-2-(1,3-thiazol-2-yl)ethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;i)N-(4-chlorobenzyl)-2-{[{2-hydroxy-2-[4-(methylsulfonyl)phenyl]ethyl}(methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide; j)N-(4-chlorobenzyl)-2-{[(2-hydroxy-2-pyridin-2-ylethyl)(methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;k)N-(4-chlorobenzyl)-2-{[(2-hydroxy-2-pyrazin-2-ylethyl)(methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;l)N-(4-chlorobenzyl)-2-{[[2-(5-cyanothien-2-yl)-2-hydroxyethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;m)N-(4-chlorobenzyl)-2-{[[2-hydroxy-2-(4-hydroxyphenyl)ethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;n)N-(4-chlorobenzyl)-2-{[[2-(2-furyl)-2-hydroxyethyl](methyl)amino]methyl}-4-{2-[methoxy(methyl)amino]-2-oxoethyl}-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;o)N-(4-chlorobenzyl)-2-{[(2-hydroxy-2-pyrazin-2-ylethyl)(methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;p)2-{[(1-benzyl-2-hydroxyethyl)(methyl)amino]methyl}-N-(4-chlorobenzyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;q)2-{[{2-[4-(acetylamino)phenyl]-2-hydroxyethyl}(methyl)amino]-methyl}-N-(4-chlorobenzyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;r)N-(4-chlorobenzyl)-2-{[[(2S)-2-hydroxy-2-pyridin-3-ylethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide; s)N-(4-chlorobenzyl)-2-{[[(2R)-2-hydroxy-2-pyridin-2-ylethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;t)N-(4-chlorobenzyl)-2-{[(2-hydroxy-2-pyrimidin-2-ylethyl)(methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;u)-(4-chlorobenzyl)-2-{[[2-hydroxy-2-(1H-indol-3-yl)ethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;v)2-{[[2-(3-aminophenyl)-2-hydroxyethyl](methyl)amino]methyl}-N-(4-chlorobenzyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide; w)2-{[[2-(1,3-Benzodioxol-5-yl)-2-hydroxyethyl](methyl)amino]methyl}-N-(4-chlorobenzyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;or x)N-(4-chlorobenzyl)-2-{[[2-hydroxy-2-(4-methoxyphenyl)ethyl]-(methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;or a pharmaceutically acceptable salt thereof.
 35. The compound a)N-(4-chlorobenzyl)-2-{[[2-hydroxy-2-(3-methoxyphenyl)ethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;b)N-(4-chlorobenzyl)-2-{[[2-(2-furyl)-2-hydroxyethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;c)N-(4-chlorobenzyl)-2-{[(2-hydroxy-2-pyrazin-2-ylethyl)(methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;d)N-(4-chlorobenzyl)-2-{[(2-hydroxy-2-pyrimidin-2-ylethyl)(methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;e)N-(4-chlorobenzyl)-2-{[[2-hydroxy-2-(1H-indol-3-yl)ethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;f)2-{[[2-(3-aminophenyl)-2-hydroxyethyl](methyl)amino]methyl}-N-(4-chlorobenzyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;g)N-(4-chlorobenzyl)-2-{[(2-hydroxy-2-pyridin-2-ylethyl)(methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;h)N-(4-chlorobenzyl)-2-{[[2-(5-cyanothien-2-yl)-2-hydroxyethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;i)N-(4-chlorobenzyl)-2-{[[2-hydroxy-2-(4-hydroxyphenyl)ethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide; j)2-{[(1-benzyl-2-hydroxyethyl)(methyl)amino]methyl}-N-(4-chlorobenzyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide; k)N-(4-chlorobenzyl)-2-{[[(2S)-2-hydroxy-2-pyridin-3-ylethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;l)N-(4-chlorobenzyl)-2-{[[(2R)-2-hydroxy-2-pyridin-2-ylethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;or m)2-{[[2-(1,3-Benzodioxol-5-yl)-2-hydroxyethyl](methyl)amino]-methyl}-N-(4-chlorobenzyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;or a pharmaceutically acceptable salt thereof.
 36. The compound a)N-(4-chlorobenzyl)-2-{[[2-hydroxy-2-(3-methoxyphenyl)ethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;b)N-(4-chlorobenzyl)-2-{[[2-(2-furyl)-2-hydroxyethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;c)N-(4-chlorobenzyl)-2-1{[(2-hydroxy-2-pyrazin-2-ylethyl)(methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;d)N-(4-chlorobenzyl)-2-{[(2-hydroxy-2-pyrimidin-2-ylethyl)(methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide; e)N-(4-chlorobenzyl)-2-{[[2-hydroxy-2-(1H-indol-3-yl)ethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;or f)2-{[[2-(3-aminophenyl)-2-hydroxyethyl](methyl)amino]methyl}-N-(4-chlorobenzyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide;or a pharmaceutically acceptable salt thereof.
 37. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable excipient.
 38. A method of treating a herpesviral infectionin a mammal, comprising: administering to an mammal in need of suchtreatment an effective amount of a compound of claim
 1. 39. The methodof claim 38 wherein the mammal is a human or an animal.
 40. The methodof claim 38 wherein the mammal is a human.
 41. The method of claim 38wherein the mammal is an animal.
 42. The method of claim 38 wherein thecompound is administered in an amount of from about 0.1 to about 300mg/kg of body weight.
 43. The method of claim 38 wherein the compound isadministered in an amount of from about 1 to about 30 mg/kg of bodyweight.
 44. A method of treating atherosclerosis or restenosiscomprising administering to a mammal in need thereof a compound ofclaim
 1. 45. A method for preparing a compound of formula I:

wherein G, R² and R³have the values described in claim 1, comprising:reacting a nucleophile with a compound of the formula III:

wherein X is a leaving group.
 46. The method of claim 45 wherein thenucleophile is of the formula NHR⁷R⁸ where R⁷ is C₁₋₇alkyl, and R⁸ isC₁₋₇alkyl which is optionally partially unsaturated and is optionallysubstituted by one or more NR¹³R¹³, OR¹⁴, SR¹⁴, S(O)_(m)R⁹, CONR¹³R¹³,CO₂R¹³, (C═O)R⁹, het, aryl, cyano, or halo substituents, and the leavinggroup X is halo.
 47. A method for preparing a compound of formula I:

wherein G, R² and R³ have the values described in claim 1 comprising:reacting a nucleophile of the formula NH₂—CH₂-G with a compound of theformula II

where X is a leaving group.
 48. A method for preparing a compound offormula A-4:

wherein R² is H, and X is a blocking group, comprising: treating acompound of formula A-3:

wherein R² and R³ are H, with a strong aprotic base and then reactingthe resulting intermediate with a formylating agent.
 49. The compound(1S)-2-(methylamino)-1-pyridin-3-ylethanol; or a salt thereof.